Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home Leukemias Solid Tumours Cancer-Prone Deep Insight Portal Teaching

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Atlas Journal

Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS

Volume 11, Number 3, Jul-Sep 2007 Previous Issue / Next Issue Genes

MSH6 (mutS homolog 6 (E. Coli)) (2p16).

Sreeparna Banerjee.

Atlas Genet Cytogenet Oncol Haematol 2006; 9 11 (3): 289-297. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/MSH6ID344ch2p16.html

LDB1 (10q24).

Takeshi Setogawa, Testu Akiyama.

Atlas Genet Cytogenet Oncol Haematol 2006; 11 (3): 298-301.[Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/LDB1ID41135ch10q24.html

INTS6 (integrator complex subunit 6) (13q14.3).

Ilse Wieland.

Atlas Genet Cytogenet Oncol Haematol 2006; 11 (3): 302-306.[Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/INTS6ID40287ch13q14.html

EPHA7 (EPH receptor A7) (6q16.1).

Haruhiko Sugimura, Hiroki Mori, Tomoyasu Bunai, Masaya Suzuki.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 307-312. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2007;3 -I URL : http://atlasgeneticsoncology.org/Genes/EPHA7ID40466ch6q16.html

RNASET2 (ribonuclease T2) (6q27).

Francesco Acquati, Paola Campomenosi.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 313-317. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/RNASET2ID518ch6q27.html

RHOB (ras homolog family, member B) (2p24.1).

Minzhou Huang, Lisa D Laury-Kleintop, George Prendergast.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 318-323. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/RHOBID42108ch2p24.html

RBM5 (RNA binding motif 5) (3p21.3).

Mirna Mourtada-Maarabouni.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 324-331. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/RBM5ID42069ch3p21.html (ras-related C3 botulinum toxin 3 (rho family, small GTP binding protein Rac3)) (17q25.3). Nora C. Heisterkamp.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 332-338. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/RAC3ID42022ch17q25.html

NUT (nuclear protein in testis) (15q14).

Anna Collin.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 339-342. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/NUTID41595ch15q14.html

MUC4 (mucin 4, cell surface associated) (3q29). Nicolas Moniaux, Pallavi Chaturvedi, Isabelle Van Seuningen, Nicole Porchet, Ajay P. Singh, Surinder K. Batra. Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 343-354. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/MUC4ID41459ch3q29.html

JAG2 (Human Jagged2) (14q32).

Atlas Genet Cytogenet Oncol Haematol 2007;3 -II Pushpankur Ghoshal, Lionel J Coignet.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 355-359. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/JAG2ID41030ch14q32.html

HSPH1 (heat shock 105kDa/110kDa protein 1) (13q12.3).

Takumi Hatayama, Nobuyuki Yamagishi.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 360-364. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/HSPH1ID40891ch13q12.html

HSPD1 (Heat Shock 60kDa Protein 1) (2q33.1).

Ahmad Faried, Leri S Faried.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 365-371. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/HSPD1ID40888ch2q33.html

HIC1 (Hypermethylated in Cancer 1) (17p13.3).

Dominique Leprince.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 372-377. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/HIC1ID40819ch17p13.html

FLCN ( gene) (17p11.2).

Laura S Schmidt.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 378-385. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/FLCNID789ch17p11.html

ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2) (8q24.12).

Mary L. Stracke, Timothy Clair.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 386-395. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/ENPP2ID40455ch8q24.html

BRD4 (bromodomain containing 4) (19p13).

Anna Collin.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 396-400. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/BRD4ID837ch19p13.html

Atlas Genet Cytogenet Oncol Haematol 2007;3 -III BCL6 (B-Cell Lymphoma 6) (3q27) - updated.

Stevan Knezevich.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 401-407. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/BCL6ID20.html

BARD1 (BRCA1 associated RING domain 1) (2q35).

Irmgard Irminger-Finger.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 408-418. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/BARD1ID756ch2q35.html

RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1) (3p25).

Max Cayo, David Yu Greentblatt, Muthusamy Kunnimalaiyaan, Herbert Chen.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 419-434. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/RAF1ID42032ch3p25.html

PSIP1 (PC4 and SFRS1 interacting protein 1) (9p22.3).

Cristina Morerio, Claudio Panarello.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 435-439. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/PSIP1ID405ch9q22.html

MIRN21 (microRNA 21) (17q23.1).

Sadan Duygu Selcuklu, Mustafa Cengiz Yakicier, Ayse Elif Erson.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 440-447. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/MIRN21ID44019ch17q23.html

KLF6 (Krüppel like factor 6) (10p15.1).

Scott L. Friedman, Goutham Narla, John A. Martignetti.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 448-455. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/KLF6ID44002ch10p15.html

IL6 (interleukin 6 (interferon beta 2)) (7p15.3).

Stefan Nagel, Roderick A F MacLeod.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 456-464. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2007;3 -IV URL : http://atlasgeneticsoncology.org/Genes/IL6ID519ch7p15.html

ALOX12 (Arachidonate 12-Lipoxygenase) Homo sapiens (17p13.1).

Sreeparna Banerjee, Asli Erdog.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 465-473. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Genes/ALOX12ID620ch17p13.html Leukaemias

t(5;12)(q31;p13) in MDS, AML and AEL.

Maria D. Odero.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 474-476. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Anomalies/t0512q31p13ID1344.html

i(8)(q10) in acute myeloid leukaemia.

David Betts.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 477-478. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Anomalies/i8q10ID1334.html Solid Tumours

Vulva and Vagina tumors: an overview.

Roberta Vanni, Giuseppina Parodo.

Atlas Genet Cytogenet Oncol Haematol 2007;11 (3): 479-484. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Tumors/VulVaginaCarcID5274.html

Carcinoma with t(15;19) translocation.

Anna Collin.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 485-488. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Tumors/Carcinot1519q14p13ID5474.html Cancer Prone Diseases

Diamond-Blackfan anemia (DBA) - updated.

Hanna T. Gazda.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 489-492. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2007;3 -V URL : http://atlasgeneticsoncology.org/Kprones/DiamondBlackfanID10040.html Deep Insights Case Reports t(16;21)(q24;q22) in therapy-related acute myelogenous leukemia arising from myelodysplastic syndrome . Paola Dal Cin, Karim Ouahchi.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 493-495. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Reports/1621DalCinID100022.html

A de novo AML with a t(1;21)(p36;q22) in an elderly patient.

Paola Dal Cin, Andrew J Yee, Bimalangshu Dey.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (3): 496-498. [Full Text] [PDF]

URL : http://atlasgeneticsoncology.org/Reports/0121DalCinID100021.html Educational Items

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Portal Teaching

For comments and suggestions or contributions, please contact us [email protected].

Atlas Genet Cytogenet Oncol Haematol 2007;3 -VI Atlas of Genetics and Cytogenetics in Oncology and Haematology

MSH6 (mutS homolog 6 (E. Coli)) Identity Other names GTBP HSAP HNPCC5 Hugo MSH6 Location 2p16 Genes flanking MSH6 in centromere to telomere direction on 2p16 are: HTLF (2p22-) (human T-cell leukemia virus enhancer factor) FBXO11 (2p16.3) (F-box protein 11) Local_order MSH6 (2p16) (mutS homolog 6 (E. coli)) LOC285053 (2p16.3) (similar to ribosomal protein L18a). KCNK12 (2p22-p21) (potassium channel, subfamily K, member 12). MSH2 (2p22-p21) (mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)). DNA/RNA Note The genes for MSH2 and MSH6 which form the major mismatch recognition MutSalpha complex functional in the mismatch repair (MMR) pathway are located within 1 Mb of each other. MSH2 and MSH6 may have been produced by duplication of a primordial mutS repair gene.

Exons are represented by gray boxes (in scale) with exon numbers on the bottom. The arrows show the ATG and the stop codons respectively.

Description MSH6 gene maps to NC_000002.10 and spans a region of 23.8 kilo bases. MSH6 has 10 exons, the sizes being 347, 197, 170, 2545, 266, 119, 89, 155, 200 and 176 bps. Transcription Human MSH6 gene is transcriptionally upregulated 2.5 fold at late G1/early S phase while the amount of protein remains unchanged during the whole cell cycle. The promoter region has a high GC content, as well as multiple start sites. Sequence analysis of 3.9 kb of the 5'-upstream region of the MSH6 gene revealed the absence of TATAA- or CAAT-boxes. Seven consensus binding sequences for the ubiquitous transcription factor Sp1 were found in the promoter region. This factor is implicated in positioning the RNA polymerase II complex at the transcriptional start sites of promoters lacking TATA- and CAAT-boxes. The proximal promoter region of MSH6 gene also contains several consensus binding sites of the embryonic TEA domain- containing factor ETF. This transcription factor has also been reported to stimulate transcription from promoters lacking the TATA box. In addition, the trancription of MSH6 gene is downregulated by CpG methylation of the promoter region. Three common polymorphic variants (-557 T G, -448 G A, and -159 C T) of the MSH6 promoter have been identified in which different Sp1 sites were inactivated by single- polymorphisms (SNPs) resulting in altered promoter activity. Pseudogene No pseudogene has been reported for the MSH6 gene. Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 3 289 Note Eukaryotic MutSalpha is a heterodimer of the 100-kDa MSH2 and the 160-kDa MSH6 that participates in the mismatch repair pathway. The are required for single base and frameshift mispair specific binding, a result consistent with the finding that tumour-derived cell lines devoid of either protein have a mutator phenotype. Description The MSH6 protein maps to NP_000170 and has 1360 amino acids. The molecular weight is 152786 Da. The protein contains a highly conserved helix-turn-helix domain associated with a Walker-A motif (an adenine nucleotide and magnesium binding motif) with ATPase activity. The breast cancer 1 gene (BRCA1) is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. This complex is called BASC, for 'BRCA1-associated genome surveillance complex and the mismatch repair protein MSH6 was found to be a part of this complex. Localisation The subcellular localisation of MSH6 is the nucleus. Function hMSH6 gene product with hMSH2, hMSH3 gene products play role in strand specific repair of DNA replication errors. Studies show that hMSH2-hMSH6 complex functions in the recognition step of the repair of base-base mismatches or single frameshifts. The ADP/ATP binding domain of the heterodimer and the associated ATPase activity function to regulate mismatch binding as a molecular switch. Both MSH2 and MSH6 can simultaneously bind ATP. The MSH6 subunit contains the high-affinity ATP and MSH2 contains a high-affinity ADP binding site. Stable binding of ATP to MSH6 results in a decreased affinity of MSH2 for ADP, and binding to mispaired DNA stabilizes the binding of ATP to MSH6. Mispair binding encourages a dual- occupancy state with ATP bound to Msh6 and Msh2; following which there is a hydrolysis-independent sliding along DNA. Subsequent steps result in the excision of the mispaired region followed by DNA synthesis and ligation. Homology H.sapiens: MSH6 (mutS homolog 6 (E. coli)). C.familiaris: LOC474585 (similar to mutS homolog 6). M.musculus: Msh6 (mutS homolog 6 (E. coli)). C.elegans: msh-6 (MSH (MutS Homolog) family). S.pombe: SPCC285.16c (hypothetical protein). S.cerevisiae: MSH6 (Mismatch repair protein). A.thaliana: MSH6 (MSH6). Mutations Note The MSH6 gene plays a role in the development of inherited cancers, especially the colorectum and endometrial cancers. Germinal MSH6 germline mutations have variable penetration. Atypical hereditary non polyposis colorectal cancer (HNPCC) can result from germline mutations in MSH6; however, disease-causing germline mutations of MSH6 are rare in HNPCC and HNPCC-like families. Other studies have indicated that germline MSH6 mutations may contribute to a subset of early-onset colorectal cancer. Somatic The involvement of somatic or epigenetic inactivation of hMSH6 is rare in colorectal cancer and missense mutations in MSH6 are often clinically innocuous or have a low penetrance. However, somatic mutations of MSH6 have been shown to confer resistance to alkylating agents such as temozolomide in malignant gliomas in vivo. This concurrently results in accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. Therefore, when MSH6 is inactivated in gliomas, there is a change in status of the alkylating agents from induction of tumour cell death to promotion of neoplastic progression. Implicated in Entity hereditary non polyposis colorectal cancer Disease Mutations in the mismatch repair genes MSH2, MSH6, MLH1 and PMS2 results in hereditary non polyposis colorectal cancer (HNPCC, Lynch syndrome). Individuals predisposed to this syndrome have increased lifetime risk of developing colorectal, endometrial and other cancers. The resulting mismatchrepair deficiency leads to

Atlas Genet Cytogenet Oncol Haematol 2007; 3 290 microsatellite instability which is the hallmark of tumors arising within this syndrome, as well as a variable proportion of sporadic tumors. Clinically, HNPCC can be divided into two subgroups: Type I: a young onset age for hereditary colorectal cancer, and carcinoma of the proximal colon. Type II: patients are susceptible to cancers in tissues such as the colon, uterus, ovary, breast, stomach, small intestine and skin. Diagnosis of classical HNPCC is based on the Amsterdam criteria: - 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; - 2 or more generation affected; - 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes.

Entity Turcot Syndrome Disease Turcot syndrome is a condition whereby central nervous system malignant tumours are associated with familial colorectal cancer. A homozygous mutation in MSH6 has been reported in a family with childhood-onset brain tumour, lymphoma, colorectal cancer, and neurofibromatosis type 1 phenotype.

Entity Colorectal cancer. Disease Mutations in four mismatch repair genes MSH2, MLH1, MSH6, and PMS2, have been convincingly linked to susceptibility of hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Of the 500 different HNPCC-associated MMR gene mutations known, approximately 10% are associated with mutations in the MSH6 gene.

Entity Endometrial cancer Disease Germline mutations in the MSH6 gene are often observed in HNPCC-like families with an increased frequency of endometrial cancer. Sequence analysis of the MSH6 coding region revealed the presence of three putative missense mutations in patients with atypical family histories that do not meet HNPCC criteria. MSH6 mutations may contribute to the etiology of double primary carcinomas of the colorectum and endometrium.

Entity Ovarian cancer Disease Late-onset endometrioid type of ovarian cancer can be linked to MSH6 germline mutations.

Entity Lung cancer Disease Early onset lung cancer (before age 50) has been associated with polymorphisms in the MSH6 gene. Cadmium, an environmental and occupational carcinogen associated with lung cancer development was shown to inhibit the ATPase activity of MSH2- MSH6 heterodimer.

Entity Breast cancer Disease Mutations in the MSH6 gene are not usually connected with breast cancer, even when associated with endometrial or colorectal cancer.

External links Nomenclature

Atlas Genet Cytogenet Oncol Haematol 2007; 3 291 Hugo MSH6 GDB MSH6 Entrez_Gene MSH6 2956 mutS homolog 6 (E. coli) Cards Atlas MSH6ID344ch2p16 GeneCards MSH6 Ensembl MSH6 Genatlas MSH6 GeneLynx MSH6 eGenome MSH6 euGene 2956 Genomic and cartography GoldenPath MSH6 - 2p16 chr2:47863790-47887595 + 2p16 (hg18-Mar_2006) Ensembl MSH6 - 2p16 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene MSH6 Gene and transcription Genbank AK130683 [ ] Genbank BC004246 [ ENTREZ ] Genbank BC071594 [ ENTREZ ] Genbank BC104665 [ ENTREZ ] Genbank D89646 [ ENTREZ ] RefSeq NM_000179 [ SRS ] NM_000179 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ] RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_022184 [ SRS ] NT_022184 [ ENTREZ ] RefSeq NW_927719 [ SRS ] NW_927719 [ ENTREZ ] AceView MSH6 AceView - NCBI Unigene Hs.445052 [ SRS ] Hs.445052 [ NCBI ] HS445052 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P52701 [ SRS] P52701 [ EXPASY ] P52701 [ INTERPRO ] PS00486 DNA_MISMATCH_REPAIR_2 [ SRS ] PS00486 Prosite DNA_MISMATCH_REPAIR_2 [ Expasy ] Prosite PS50812 PWWP [ SRS ] PS50812 PWWP [ Expasy ] Interpro IPR000432 MutS_C [ SRS ] IPR000432 MutS_C [ EBI ] Interpro IPR007860 MutS_II [ SRS ] IPR007860 MutS_II [ EBI ] Interpro IPR007696 MutS_III [ SRS ] IPR007696 MutS_III [ EBI ] Interpro IPR007861 MutS_IV [ SRS ] IPR007861 MutS_IV [ EBI ] Interpro IPR007695 MutS_N [ SRS ] IPR007695 MutS_N [ EBI ] Interpro IPR000313 PWWP [ SRS ] IPR000313 PWWP [ EBI ] CluSTr P52701 PF01624 MutS_I [ SRS ] PF01624 MutS_I [ Sanger ] pfam01624 [ NCBI-CDD ] Pfam PF05188 MutS_II [ SRS ] PF05188 MutS_II [ Sanger ] pfam05188 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 292 Pfam PF05192 MutS_III [ SRS ] PF05192 MutS_III [ Sanger ] pfam05192 [ NCBI-CDD ] Pfam PF05190 MutS_IV [ SRS ] PF05190 MutS_IV [ Sanger ] pfam05190 [ NCBI-CDD ] Pfam PF00488 MutS_V [ SRS ] PF00488 MutS_V [ Sanger ] pfam00488 [ NCBI-CDD ] Pfam PF00855 PWWP [ SRS ] PF00855 PWWP [ Sanger ] pfam00855 [ NCBI-CDD ] Smart SM00534 MUTSac [EMBL] Smart SM00533 MUTSd [EMBL] Smart SM00293 PWWP [EMBL] Prodom PD001263 MutS_C[INRA-Toulouse] P52701 MSH6_HUMAN [ Domain structure ] P52701 MSH6_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P52701 HPRD P52701 Protein Interaction databases DIP P52701 IntAct P52701 Polymorphism : SNP, mutations, diseases OMIM 600678 [ map ] GENECLINICS 600678 SNP MSH6 [dbSNP-NCBI] SNP NM_000179 [SNP-NCI] SNP MSH6 [GeneSNPs - Utah] MSH6] [HGBASE - SRS] HAPMAP MSH6 [HAPMAP] COSMIC MSH6 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family MSH6 [UCSC Family Browser] Browser SOURCE NM_000179 SMD Hs.445052 SAGE Hs.445052 GO nucleotide binding [Amigo] nucleotide binding GO magnesium ion binding [Amigo] magnesium ion binding GO four-way junction DNA binding [Amigo] four-way junction DNA binding purine-specific mismatch DNA N-glycosylase activity [Amigo] purine- GO specific mismatch base pair DNA N-glycosylase activity GO nuclear chromatin [Amigo] nuclear chromatin GO chromatin binding [Amigo] chromatin binding GO damaged DNA binding [Amigo] damaged DNA binding GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO ATP binding [Amigo] ATP binding GO nucleus [Amigo] nucleus GO base-excision repair [Amigo] base-excision repair GO mismatch repair [Amigo] mismatch repair GO mismatch repair [Amigo] mismatch repair

Atlas Genet Cytogenet Oncol Haematol 2007; 3 293 GO mismatch repair [Amigo] mismatch repair GO determination of adult life span [Amigo] determination of adult life span DNA damage response, signal transduction resulting in induction of apoptosis GO [Amigo] DNA damage response, signal transduction resulting in induction of apoptosis GO response to UV [Amigo] response to UV somatic hypermutation of immunoglobulin genes [Amigo] somatic hypermutation of GO immunoglobulin genes somatic recombination of immunoglobulin gene segments [Amigo] somatic GO recombination of immunoglobulin gene segments GO ATPase activity [Amigo] ATPase activity GO mismatched DNA binding [Amigo] mismatched DNA binding GO guanine/thymine mispair binding [Amigo] guanine/thymine mispair binding dinucleotide insertion or deletion binding [Amigo] dinucleotide insertion or deletion GO binding GO single guanine insertion binding [Amigo] single guanine insertion binding GO single thymine insertion binding [Amigo] single thymine insertion binding GO MutSalpha complex [Amigo] MutSalpha complex GO oxidized purine DNA binding [Amigo] oxidized purine DNA binding GO MutLalpha complex binding [Amigo] MutLalpha complex binding GO protein homodimerization activity [Amigo] protein homodimerization activity GO ADP binding [Amigo] ADP binding GO isotype switching [Amigo] isotype switching negative regulation of DNA recombination [Amigo] negative regulation of DNA GO recombination PubGene MSH6 Other databases Probes Probe MSH6 Related clones (RZPD - Berlin) PubMed PubMed 75 Pubmed reference(s) in LocusLink Bibliography GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Palombo, F.; Gallinari, P.; Iaccarino, I.; Lettieri, T.; Hughes, M.; D'Arrigo, A.; Truong, O.; Hsuan, J. J.; Jiricny, J. Science. 1995; 268: 1912-1914. Medline 7604265

Mutations of GTBP in genetically unstable cells. Papadopoulos N, Nicolaides NC, Liu B, Parsons R, Lengauer C, Palombo F, D'Arrigo A, Markowitz S, Willson JK, Kinzler KW, et al. Science. 1995; 268(5219):1915-1917. Medline 7604266 hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R. Proc Natl Acad Sci U S A. 1996; 93(24):13629-13634. Medline 8942985

Atlas Genet Cytogenet Oncol Haematol 2007; 3 294

The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch. Gradia, S.; Acharya, S.; Fishel, R. Cell. 1997; 91(7):995-1005. Medline 9428522 hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Gradia S, Subramanian D, Wilson T, Acharya S, Makhov A, Griffith J, Fishel R. Mol Cell. 1999; 3(2):255-261. Medline 10078208

Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium? Charames GS, Millar AL, Pal T, Narod S, Bapat B. Hum Genet. 2000; 107(6):623-629. Medline 11153917

BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. Genes Dev. 2000; 14(8):927-939. Medline 10783165

Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation. Plaschke J, Kruger S, Pistorius S, Theissig F, Saeger HD, Schackert HK. Int J Cancer. 2002; 97(5):643-648. Medline 11807791

Ovarian cancer of endometrioid type as part of the MSH6 gene mutation phenotype. Suchy J, Kurzawski G, Jakubowska A, Lubinski J. J Hum Genet. 2002; 47(10):529-531. Medline 12376742

Identification and functional characterization of the promoter region of the human MSH6 gene. Szadkowski M, Jiricny J. Genes Cancer. 2002; 33(1):36-46. Medline 11746986

Regulation of the human MSH6 gene by the Sp1 transcription factor and alteration of promoter activity and expression by polymorphisms. Gazzoli I, Kolodner RD. Mol Cell Biol. 2003; 23(22):7992-8007. Medline 14585961

MSH6 germline mutations are rare in colorectal cancer families. Peterlongo P, Nafa K, Lerman GS, Glogowski E, Shia J, Ye TZ, Markowitz AJ, Guillem JG, Kolachana P, Boyd JA, Offit K, Ellis NA. Int J Cancer. 2003; 107(4):571-579. Medline 14520694

MSH6 missense mutations are often associated with no or low cancer susceptibility. Kariola R, Hampel H, Frankel WL, Raevaara TE, de la Chapelle A, Nystrom-Lahti M.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 295 Br J Cancer. 2004; 91(7):1287-1292. Medline 15354210

Cadmium inhibits mismatch repair by blocking the ATPase activity of the MSH2-MSH6 complex. Banerjee S, Flores-Rozas H. Nucleic Acids Res. 2005; 33(4):1410-1419. Medline 15746000

A homozygous mutation in MSH6 causes Turcot syndrome. Hegde MR, Chong B, Blazo ME, Chin LH, Ward PA, Chintagumpala MM, Kim JY, Plon SE, Richards CS. Clin Cancer Res. 2005; 11(13):4689-4693. Medline 16000562

Lynch syndrome genes. Peltomaki P. Fam Cancer. 2005; 4(3):227-232. Medline 16136382

Inherited susceptibility to colorectal cancer. Rowley PT. Annu Rev Med. 2005; 56:539-554. Medline 15660526

Low prevalence of germline hMSH6 mutations in colorectal cancer families from Spain. Sanchez de Abajo A, de la Hoya M, Tosar A, Godino J, Fernandez JM, Asenjo JL, Villamil BP, Segura PP, Diaz-Rubio E, Caldes T. World J Gastroenterol. 2005; 11(37):5770-5776. Medline 16270383

No MSH6 germline mutations in breast cancer families with colorectal and/or endometrial cancer. Vahteristo P, Ojala S, Tamminen A, Tommiska J, Sammalkorpi H, Kiuru-Kuhlefelt S, Eerola H, Aaltonen LA, Aittomaki K, Nevanlinna H. J Med Genet. 2005; 42(4):e22. Medline 15805151

The genetics of HNPCC: application to diagnosis and screening. Abdel-Rahman WM, Mecklin JP, Peltomaki P. Crit Rev Oncol Hematol. 2006; 58(3):208-220. Medline 16434208

Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. Barnetson RA, Tenesa A, Farrington SM, Nicholl ID, Cetnarskyj R, Porteous ME, Campbell H, Dunlop MG. N Engl J Med. 2006; 354(26):2751-2763. Medline 16807412

A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Hunter C, Smith R, Cahill DP, Stephens P, Stevens C, Teague J, Greenman C, Edkins S, Bignell G, Davies H, et al.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 296 Cancer Res. 2006; 66(8):3987-3991. Medline 16618716

The multifaceted mismatch-repair system. Jiricny J. Nat Rev Mol Cell Biol. 2006; 7(5):335-346. Medline 16612326

DNA repair and cell cycle control genes and the risk of young-onset lung cancer. Landi S, Gemignani F, Canzian F, Gaborieau V, Barale R, Landi D, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Gioia-Patricola L, Hall J, Boffetta P, Hung RJ, Brennan P. Cancer Res. 2006; 66(22):11062-11069. Medline 17108146

Inhibition of Msh6 ATPase activity by mispaired DNA induces a Msh2(ATP)-Msh6(ATP) state capable of hydrolysis-independent movement along DNA. Mazur DJ, Mendillo ML, Kolodner RD. Mol Cell. 2006; 22(1):39-49. Medline 16600868

MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease. Pinto C, Veiga I, Pinheiro M, Mesquita B, Jeronimo C, Sousa O, Fragoso M, Santos L, Moreira-Dias L, Baptista M, Lopes C, Castedo S, Teixeira MR. Br J Cancer. 2006; 95(6):752-756. Medline 16940983

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 11-2006 Sreeparna Banerjee Citation This paper should be referenced as such : Banerjee S . MSH6 (mutS homolog 6 (E. Coli)). Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Genes/MSH6ID344ch2p16.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 297 Atlas of Genetics and Cytogenetics in Oncology and Haematology

LDB1 Identity Other names CLIM2 NLI Hugo LDB1 Location 10q24 DNA/RNA Description 7kb; 11exons Transcription 2292 mRNA Protein

Description 375 amino acids; 42.8 kDa protein Expression Widely expressed Localisation Nuclear Function LDB1 is a nuclear protein that contains an N-terminal dimerization domain and a C- terminal LIM interaction domain (LID). LDB1 binds to LIM-homeodomain (LIM-HD) and LIM-only (LMO) proteins. It acts as an adaptor protein that mediates interactions between different classes of transcription factors and their cofactors. LDB1 forms a complex with LKB1, LMO4, and GATA-6. The tumor suppressor LKB1is mutated in PeutzJeghers syndrome and various sporadic cancers. A complex containing LDB1, LKB1, LMO4, and GATA-6 induces cyclin-dependent kinase inhibitor p21 expression. Targeted deletion of the Ldb1 gene in mice displays multiple developmental defects that reveal a requirement of Ldb1 gene during normal development. Implicated in Entity Oral squamous cell carcinoma Oncogenesis LDB1 and are frequently detected in less-differentiated and metastasized squamous carcinoma, and overexpressed at the carcinoma invasive front.

External links Nomenclature Hugo LDB1 GDB LDB1 Entrez_Gene LDB1 8861 LIM domain binding 1 Cards Atlas LDB1ID41135ch10q24 GeneCards LDB1 Ensembl LDB1 Genatlas LDB1 GeneLynx LDB1 eGenome LDB1 euGene 8861

Atlas Genet Cytogenet Oncol Haematol 2007; 3 298 Genomic and cartography GoldenPath LDB1 - 10q24 chr10:103857317-103864692 - 10q24-q25 (hg18-Mar_2006) Ensembl LDB1 - 10q24-q25 [CytoView] NCBI Mapview OMIM Disease map [OMIM]

HomoloGene LDB1 Gene and transcription Genbank AB016485 [ ENTREZ ] Genbank AB250384 [ ENTREZ ] Genbank AF064491 [ ENTREZ ] Genbank AF068652 [ ENTREZ ] Genbank BC000482 [ ENTREZ ] RefSeq NM_003893 [ SRS ] NM_003893 [ ENTREZ ] RefSeq AC_000053 [ SRS ] AC_000053 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_030059 [ SRS ] NT_030059 [ ENTREZ ] RefSeq NW_924884 [ SRS ] NW_924884 [ ENTREZ ] AceView LDB1 AceView - NCBI Unigene Hs.454418 [ SRS ] Hs.454418 [ NCBI ] HS454418 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O75479 [ SRS] O75479 [ EXPASY ] O75479 [ INTERPRO ] Interpro IPR002691 LIM_bd [ SRS ] IPR002691 LIM_bd [ EBI ] CluSTr O75479 PF01803 LIM_bind [ SRS ] PF01803 LIM_bind [ Sanger ] pfam01803 [ NCBI-CDD Pfam ] Blocks O75479 HPRD O75479 Protein Interaction databases DIP O75479 IntAct O75479 Polymorphism : SNP, mutations, diseases OMIM 603451 [ map ] GENECLINICS 603451 SNP LDB1 [dbSNP-NCBI] SNP NM_003893 [SNP-NCI] SNP LDB1 [GeneSNPs - Utah] LDB1] [HGBASE - SRS] HAPMAP LDB1 [HAPMAP] General knowledge Family LDB1 [UCSC Family Browser] Browser SOURCE NM_003893 SMD Hs.454418 SAGE Hs.454418

Atlas Genet Cytogenet Oncol Haematol 2007; 3 299 GO transcription activity [Amigo] transcription cofactor activity GO transcription corepressor activity [Amigo] transcription corepressor activity GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO multicellular organismal development [Amigo] multicellular organismal development GO multicellular organismal development [Amigo] multicellular organismal development GO anterior/posterior axis specification [Amigo] anterior/posterior axis specification GO gastrulation (sensu Mammalia) [Amigo] gastrulation (sensu Mammalia) GO Wnt receptor signaling pathway [Amigo] Wnt receptor signaling pathway GO neuron differentiation [Amigo] neuron differentiation GO LIM domain binding [Amigo] LIM domain binding GO LIM domain binding [Amigo] LIM domain binding GO protein homodimerization activity [Amigo] protein homodimerization activity GO protein complex [Amigo] protein complex negative regulation of erythrocyte differentiation [Amigo] negative regulation of GO erythrocyte differentiation negative regulation of transcription, DNA-dependent [Amigo] negative regulation of GO transcription, DNA-dependent BIOCARTA Multi-step Regulation of Transcription by Pitx2 [Genes] PubGene LDB1 Other databases Probes Probe LDB1 Related clones (RZPD - Berlin) PubMed PubMed 27 Pubmed reference(s) in LocusLink Bibliography Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Agulnick AD, Taira M, Breen JJ, Tanaka T, Dawid IB, Westphal H Nature 1996; 384: 270-272. Medline 8918878

A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins. Bach I, Carriere C, Ostendorff HP, Andersen B, Rosenfeld MG. Genes Dev 1997; 11: 1370-1380. Medline 9192866

Functional analysis of the nuclear LIM domain interactor NLI. Jurata LW, Gill GN Mol Cell Biol 1997;17: 5688-5698. Medline 9315627

The LIM-domain binding protein Ldb1 and its partner LMO2 act as negative regulators of erythroid differentiation. Visvader JE, Mao X, Fujiwara Y, Hahm K, Orkin SH Proc Natl Acad Sci USA 1997; 94: 13707-13712. Medline 9391090

Atlas Genet Cytogenet Oncol Haematol 2007; 3 300 Ssdp proteins interact with the LIM-domain-binding protein Ldb1 to regulate development. Chen L, Segal D, Hukriede NA, Podtelejnikov AV, Bayarsaihan D, Kennison JA, Ogryzko VV, Dawid IB, Westphal H Proc Natl Acad Sci USA 2002; 99: 14320-14325. Medline 12381786

LIM-domain-binding protein 1: a multifunctional cofactor that interacts with diverse proteins. Matthews JM, Visvader JE EMBO Rep 2003; 4: 1132-1137. Review. Medline 14647207

The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity. Mizunuma H, Miyazawa J, Sanada K, Imai K Br J Cancer 2003; 88: 1543-1548. Medline 12771919

Functional ablation of the mouse Ldb1 gene results in severe patterning defects during gastrulation. Mukhopadhyay M, Teufel A, Yamashita T, Agulnick AD, Chen L, Downs KM, Schindler A, Grinberg A, Huang SP, Dorward D, Westphal H Development 2003; 130: 495-505. Medline 12490556

The tumor suppressor LKB1 induces p21 expression in collaboration with LMO4, GATA-6, and Ldb1. Setogawa T, Shinozaki-Yabana S, Masuda T, Matsuura K, Akiyama T Biochem Biophys Res Commun 2006; 343: 1186-1190. Medline 16580634

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 11-2006 Takeshi Setogawa, Testu Akiyama Citation This paper should be referenced as such : Setogawa T, Akiyama T . LDB1. Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Genes/LDB1ID41135ch10q24.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 301 Atlas of Genetics and Cytogenetics in Oncology and Haematology

INTS6 (integrator complex subunit 6) Identity Other names DICE1 deleted in cancer 1 DBI-1 DDX26 INT6 Hugo INTS6 Location 13q14.3 DNA/RNA Description The DICE1 gene consists of 18 exons and contains a GpC-rich promoter. Transcription A major transcript of 4.4 kb and a minor transcript of 6.9 kb was detected in fetal and adult tissues. In adult heart, brain and skeletal muscle an additional smaller transcript of 4 kb has been detected by Northern blot analysis. The DICE1 cDNA consists of 3665 bp with a coding sequence of 2661 bp; an alternatively spliced variant generated by skipping of exon 3 has been detected specifically in brain. Pseudogene Presumably LOC285634 at 5p13.1 Protein

Description For the DICE1 protein 887 amino acids were predicted. A protein of approximately 100 kDaltons was detected by coupled in vitro transcription and translation. The Int6 protein was purified as an approximately 110 kDaltons polypeptide component of a nuclear Integrator complex. Localisation Mainly nuclear localisation Function Predicted motifs of DICE1 protein were a von willebrand factor a (VWFA) domain of nuclear proteins, nuclear sorting signals and a DEAD box of ATP-dependent . Ectopic expression of DICE1 cDNA in tumour cells suppresses colony formation and in cell culture. The Int6 protein was purified as a subunit of a RNA polymerase II multiprotein complex with roles in transcriptional regulation and RNA processing. Homology Weak homology to members of the superfamily II Mutations Note Mutations in the coding sequence of DICE1/DDX26 have been infrequently detected in tumour cells. Somatic Frequent loss of heterozygosity (LOH) has been observed in lung, esophageal and prostate carcinomas. Promoter hypermethylation concomitant with reduced mRNA expression has been observed in lung and prostate carcinomas. In esophageal squamous cell carcinomas missense mutations V431I, R658Q have been detected. In prostate cancer cell line LNCaP missense mutation D546G has been described. Implicated in Entity Functional inactivation of the DICE1 gene has been implicated in tumorigenesis of sporadic lung carcinomas, esophagus carcinomas, prostate carcinomas and possibly other sporadic carcinomas. Abnormal A 6.3 kb fusion cDNA of a Notch-like with Dice1 cDNA (DBI-1) was detected in mouse

Atlas Genet Cytogenet Oncol Haematol 2007; 3 302 Protein cell line TC4. Overexpression of DBI-1 cDNA in IGF-IR transformed mouse cells compromised the mitogenic response to IGF-1 and interfered with anchorage- independent growth. Oncogenesis Downregulation of DICE1 mRNA was detected in 7 of 8 non-small cell lung carcinoma cell lines by Northern blot analysis. Microdissected non-small cell lung carcinomas showed reduced or absent expression of DICE1 mRNA by RT-PCR. Promoter hypermethylation was found in tumour cells with downregulated DICE1 expression. Aberrantly sized transcripts were detected in two non-small cell lung carcinoma cell lines. A reduced DICE1 expression was also observed in prostate cancer cell lines DU145 and LNCaP by real-time RT-PCR. DICE1 promoter hypermethylation was detected in 6 of 10 microdissected prostate cancer samples. Ectopic expression of DICE1 cDNA inhibited colony formation of human non-small cell lung carcinoma cell lines and prostate carcinoma cell lines and suppressed anchorage-independent growth of IGF-IR transformed mouse cells.

External links Nomenclature Hugo INTS6 GDB INTS6 Entrez_Gene INTS6 26512 integrator complex subunit 6 Cards Atlas INTS6ID40287ch13q14 GeneCards INTS6 Ensembl INTS6 Genatlas INTS6 GeneLynx INTS6 eGenome INTS6 euGene 26512 Genomic and cartography GoldenPath INTS6 - 13q14.3 chr13:50833703-50925276 - 13q14.12-q14.2 (hg18-Mar_2006) Ensembl INTS6 - 13q14.12-q14.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene INTS6 Gene and transcription Genbank AF097645 [ ENTREZ ] Genbank AF141326 [ ENTREZ ] Genbank AK074946 [ ENTREZ ] Genbank AK096696 [ ENTREZ ] Genbank AK128795 [ ENTREZ ] RefSeq NM_001039937 [ SRS ] NM_001039937 [ ENTREZ ] RefSeq NM_001039938 [ SRS ] NM_001039938 [ ENTREZ ] RefSeq NM_012141 [ SRS ] NM_012141 [ ENTREZ ] RefSeq AC_000056 [ SRS ] AC_000056 [ ENTREZ ] RefSeq NC_000013 [ SRS ] NC_000013 [ ENTREZ ] RefSeq NT_024524 [ SRS ] NT_024524 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 303 RefSeq NW_925473 [ SRS ] NW_925473 [ ENTREZ ] AceView INTS6 AceView - NCBI Unigene Hs.439440 [ SRS ] Hs.439440 [ NCBI ] HS439440 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q9UL03 [ SRS] Q9UL03 [ EXPASY ] Q9UL03 [ INTERPRO ] Prosite PS50234 VWFA [ SRS ] PS50234 VWFA [ Expasy ] Interpro IPR000629 DEAD_box [ SRS ] IPR000629 DEAD_box [ EBI ] Interpro IPR002035 VWF_A [ SRS ] IPR002035 VWF_A [ EBI ] CluSTr Q9UL03 Smart SM00327 VWA [EMBL] Blocks Q9UL03 HPRD Q9UL03 Protein Interaction databases DIP Q9UL03 IntAct Q9UL03 Polymorphism : SNP, mutations, diseases OMIM 604331 [ map ] GENECLINICS 604331 SNP INTS6 [dbSNP-NCBI] SNP NM_001039937 [SNP-NCI] SNP NM_001039938 [SNP-NCI] SNP NM_012141 [SNP-NCI] SNP INTS6 [GeneSNPs - Utah] INTS6] [HGBASE - SRS] HAPMAP INTS6 [HAPMAP] COSMIC INTS6 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family INTS6 [UCSC Family Browser] Browser SOURCE NM_001039937 SOURCE NM_001039938 SOURCE NM_012141 SMD Hs.439440 SAGE Hs.439440 GO nucleic acid binding [Amigo] nucleic acid binding GO transmembrane receptor activity [Amigo] transmembrane receptor activity GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO nucleus [Amigo] nucleus GO ATP-dependent helicase activity [Amigo] ATP-dependent helicase activity GO snRNA processing [Amigo] snRNA processing GO integrator complex [Amigo] integrator complex PubGene INTS6 Other databases Probes

Atlas Genet Cytogenet Oncol Haematol 2007; 3 304 Probe INTS6 Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in LocusLink Bibliography DBI-1, a novel gene related to the Notch family, modulates mitogenic response to insulin-like growth factor 1. Hoff HBIII, Tresini M, Li S, Sell C Exp Cell Res 1998; 238: 359-370 Medline 9473344

Analysis of the mouse MAPIB gene identifies a highly conserved 4.3 kb 3¹untranslated region and provides evidence against the proposed structure of DBI-1 cDNA. Meixner A, Wiche G, Propst F Biochim Biophys Acta 1999; 1445; 345-350 Medline 10366719

Isolation of DICE1: A gene frequently affected by LOH and downregulated in lung carcinomas. Wieland I, Arden KC, Michels D, Klein-Hitpass L, Böhm M, Viars CS, Weidle UH Oncogene 1999; 18: 4530-4537 Medline 10467397

Molecular characterization of the DICE1 (DDX26) in lung carcinomas. Wieland I, Röpke A, Stumm M, Sell C, Weidle UH, Wieacker PF Oncol Res 2001; 12: 491-500. Medline 11593297

Distribution and evolution of von willebrand/integrin a domains: widely dispersed domains with roles in cell adhesion and elsewhere. Whittaker CA and Hynes RO Mol Biol Cell 2002; 13: 3369-3387. (REVIEW) Medline 12388743

Allelic loss on 13q14 and mutation in deleted in cancer 1 gene in esophageal squamous cell carcinoma. Li WJ, Hu N, Su H, Wang C, Goldstein AM, Wang Y, Emmert-Buck MR, Roth MJ, Guo WJ, Taylor PR Oncogene 2003; 22: 314-318. Medline 12527901

Ectopic expression of DICE1 suppresses tumor cell growth. Wieland I, Sell C, Weidle UH, Wieacker P Oncol Rep 2004; 12: 207-211. Medline 15254679

Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C- terminal repeat of RNA polymerase II. Baillat D, Hakimi MA, Naar AM, Shilatifard A, Cooch N, Shiekhattar R Cell 2005; 123:265-276 Medline 16239144

Absence of mutations in DICE1/DDX26 gene in human cancer cell lines with frequent 13q14 deletions. Hernandes M, Papadopoulos N, Almeida TA Cancer Genet Cytogenet 2005; 163:91-92.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 305 Medline 16271964

Promoter CpG hypermethylation downregulates DICE1 expression in prostate cancer. Röpke A, Buthz P, Böhm M, Seger J, Wieland I, Allhoff EP, Wieacker P Oncogene 2005; 24: 6667-6675. Medline 16007164

Deleted in cancer 1 (DICE1) is an essential protein controlling the topology of the inner mitochondrial membrane in C. elegans. Han SM, Lee TH, Mun Jy, Kim MJ, Kritikou EA, Lee SJ, Han SS, Hengartner MO, Koo HS. Medline 16914495

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 11-2006 Ilse Wieland Citation This paper should be referenced as such : Wieland I . INTS6 (integrator complex subunit 6). Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Genes/INTS6ID40287ch13q14.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 306

Atlas of Genetics and Cytogenetics in Oncology and Haematology

EPHA7 (EPH receptor A7)

Identity Other names EHK3 HEK11 Hugo EPHA7 Location 6q16.1 DNA/RNA Description The EPHA7 gene maps on chromosome 6q16.1 spanning 178,134 bp. it contains 17 exons, the orientation of the gene is complement. Transcription rTanscript of 5,229 bp. Protein

Description EPHA7 encodes 998 amino acids, theoretical pI is 5.58, theoretical molecular weight is 112 KDa, , catalytic domain, sterile alpha motif, 2 fibronectin type 3 domains, ephrin receptor ligand binding domain and tumor necrosis factor receptor domain. Expression in brain, skeletal muscle, lung, kidney, liver, colorectum and nerve system. Localisation Located in the membrane. Function ATP Binding, ephrin receptor activity, nucleotide binding, protein binding, receptor activity, activity. Homology Homo sapiens: EPHA5 isoform b [NP_872272] (64%), EPHA5 isoform a [NP_004430] (63%), EPHA4 [NP_004429] (63%), EPHA3 [AAG43576] (63%). Implicated in Entity Colorectal cancer Note A significant reduction of EphA7 expression in human colorectal cancers was shown using semiquantitative reverse transcription-polymerase chain reaction analysis in 59 colorectal cancer tissues, compared to corresponding normal mucosas (P=0.008), and five colon cancer cell lines. To investigate the mechanism of EphA7 downregulation in colorectal cancer, we examined the methylation status of the 5'CpGislandaroundthe

Atlas Genet Cytogenet Oncol Haematol 2007; 3 307 translation start site in five colon cancer cell lines using restriction , methylation-specific PCR, and bisulfite sequencing and found evidence of aberrant methylation. The expression of EphA7 in colon cancer cell lines was restored after treatment with 5-aza-2'-deoxycytidine. Analysis of methylation status in totally 75 tumors compared to clinicopathological parameters revealed that hypermethylation of colorectal cancers was more frequent in male than in female, and in moderately differentiated than in well-differentiated adenocarcinomas. There was a tendency that hypermethylation in rectal cancers was more frequent than in colon cancers. Hypermethylation was also observed in colorectal adenomas. This is the first report describing the downregulation of an Eph family gene in a solid tumor via aberrant 5'CpG island methylation. It provides the evidence that EphA7 gene is involved in human colorectal .

External links Nomenclature Hugo EPHA7 GDB EPHA7 Entrez_Gene EPHA7 2045 EPH receptor A7 Cards Atlas EPHA7ID40466ch6q16 GeneCards EPHA7 Ensembl EPHA7 Genatlas EPHA7 GeneLynx EPHA7 eGenome EPHA7 euGene 2045 Genomic and cartography GoldenPath EPHA7 - 6q16.1 chr6:94007862-94185993 - 6q16.1 (hg18-Mar_2006) Ensembl EPHA7 - 6q16.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene EPHA7 Gene and transcription Genbank AB209269 [ ENTREZ ] Genbank AL699163 [ ENTREZ ] Genbank BC027940 [ ENTREZ ] Genbank BC126125 [ ENTREZ ] Genbank BC126151 [ ENTREZ ] RefSeq NM_004440 [ SRS ] NM_004440 [ ENTREZ ] RefSeq AC_000049 [ SRS ] AC_000049 [ ENTREZ ] RefSeq NC_000006 [ SRS ] NC_000006 [ ENTREZ ] RefSeq NT_007299 [ SRS ] NT_007299 [ ENTREZ ] RefSeq NW_923184 [ SRS ] NW_923184 [ ENTREZ ] AceView EPHA7 AceView - NCBI Unigene Hs.73962 [ SRS ] Hs.73962 [ NCBI ] HS73962 [ spliceNest ] Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2007; 3 308 SwissProt Q15375 [ SRS] Q15375 [ EXPASY ] Q15375 [ INTERPRO ] Prosite PS01186 EGF_2 [ SRS ] PS01186 EGF_2 [ Expasy ] Prosite PS50853 FN3 [ SRS ] PS50853 FN3 [ Expasy ] PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP [ Prosite Expasy ] PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM [ Prosite Expasy ] PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 PROTEIN_KINASE_TYR [ Prosite Expasy ] PS00790 RECEPTOR_TYR_KIN_V_1 [ SRS ] PS00790 Prosite RECEPTOR_TYR_KIN_V_1 [ Expasy ] PS00791 RECEPTOR_TYR_KIN_V_2 [ SRS ] PS00791 Prosite RECEPTOR_TYR_KIN_V_2 [ Expasy ] Prosite PS50105 SAM_DOMAIN [ SRS ] PS50105 SAM_DOMAIN [ Expasy ] Interpro IPR013032 EGF_like_reg [ SRS ] IPR013032 EGF_like_reg [ EBI ] Interpro IPR001090 Eph_rcpt_lig_bd [ SRS ] IPR001090 Eph_rcpt_lig_bd [ EBI ] Interpro IPR003961 FN_III [ SRS ] IPR003961 FN_III [ EBI ] Interpro IPR008957 FN_III-like [ SRS ] IPR008957 FN_III-like [ EBI ] Interpro IPR003962 FnIII_subd [ SRS ] IPR003962 FnIII_subd [ EBI ] Interpro IPR009030 Growth_fac_rcpt [ SRS ] IPR009030 Growth_fac_rcpt [ EBI ] Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ] Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR001660 SAM [ SRS ] IPR001660 SAM [ EBI ] Interpro IPR011510 SAM_2 [ SRS ] IPR011510 SAM_2 [ EBI ] Interpro IPR010993 SAM_homology [ SRS ] IPR010993 SAM_homology [ EBI ] Interpro IPR013761 SAM_type [ SRS ] IPR013761 SAM_type [ EBI ] Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ] Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ] Interpro IPR001426 YKase_receptorV [ SRS ] IPR001426 YKase_receptorV [ EBI ] CluSTr Q15375 PF01404 Ephrin_lbd [ SRS ] PF01404 Ephrin_lbd [ Sanger ] pfam01404 [ NCBI- Pfam CDD ] Pfam PF00041 fn3 [ SRS ] PF00041 fn3 [ Sanger ] pfam00041 [ NCBI-CDD ] PF07714 Pkinase_Tyr [ SRS ] PF07714 Pkinase_Tyr [ Sanger ] pfam07714 [ Pfam NCBI-CDD ] Pfam PF07647 SAM_2 [ SRS ] PF07647 SAM_2 [ Sanger ] pfam07647 [ NCBI-CDD ] Smart SM00615 EPH_lbd [EMBL] Smart SM00060 FN3 [EMBL] Smart SM00454 SAM [EMBL] Smart SM00219 TyrKc [EMBL] Prodom PD001495 Ephrin_receptor[INRA-Toulouse] Q15375 EPHA7_HUMAN [ Domain structure ] Q15375 EPHA7_HUMAN [ Prodom sequences sharing at least 1 domain ] Prodom PD001495[INRA-Toulouse] Q15375 EPHA7_HUMAN [ Domain structure ] Q15375 EPHA7_HUMAN [ Prodom sequences sharing at least 1 domain ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 309 Blocks Q15375 HPRD Q15375 Protein Interaction databases DIP Q15375 IntAct Q15375 Polymorphism : SNP, mutations, diseases OMIM 602190 [ map ] GENECLINICS 602190 SNP EPHA7 [dbSNP-NCBI] SNP NM_004440 [SNP-NCI] SNP EPHA7 [GeneSNPs - Utah] EPHA7] [HGBASE - SRS] HAPMAP EPHA7 [HAPMAP] COSMIC EPHA7 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family EPHA7 [UCSC Family Browser] Browser SOURCE NM_004440 SMD Hs.73962 SAGE Hs.73962 2.7.10.1 [ -SRS ] 2.7.10.1 [ Brenda-SRS ] 2.7.10.1 [ KEGG ] 2.7.10.1 [ Enzyme WIT ] GO nucleotide binding [Amigo] nucleotide binding GO receptor activity [Amigo] receptor activity GO ephrin receptor activity [Amigo] ephrin receptor activity GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO protein amino acid phosphorylation [Amigo] protein amino acid phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway GO [Amigo] transmembrane receptor protein tyrosine kinase signaling pathway GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane GO transferase activity [Amigo] transferase activity PubGene EPHA7 Other databases Probes Probe EPHA7 Related clones (RZPD - Berlin) PubMed PubMed 23 Pubmed reference(s) in LocusLink Bibliography Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Holmberg J, DL Clarke, and J Frisen. Nature. 2000; 408(6809): 203-206. Medline 11089974

Differential of Eph receptors and ephrins in benign human tissues and

Atlas Genet Cytogenet Oncol Haematol 2007; 3 310 cancers. Hafner C.,Schmitz G.,Meyer S.,Bataille F.,Hau P.,Langmann T.,Dietmaier W.,Landthaler M.,Vogt T. Clin Chem. 2004; 50(3): 490-499. Medline 14726470

Downregulation of EphA7 by hypermethylation in colorectal cancer. Wang J,Kataoka H,Suzuki M,Sato N,Nakamura R,Tao H,Maruyama K, Isogaki J,Kanaoka S,Ihara M,Tanaka M,Kanamori M, Nakamura T, Shinmura K, Sugimura H. Oncogene. 2005; 24(36): 5637-5647. Medline 16007213

Inhibition of EphA7 up-regulation after spinal cord injury reduces apoptosis and promotes locomotor recovery. Figueroa JD, Benton RL, Velazquez I, Torrado AI, Ortiz CM, Hernandez CM, Diaz JJ, Magnuson DS, Whittemore SR, Miranda JD. J Neurosci Res. 2006; 84(7): 1438-1451. Medline 16983667

Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer. Hafner C.,Becker B.,Landthaler M., Vogt T. Mod Pathol. 2006; 19(10): 1369-1377. Medline 16862074

Absence of tyrosine kinase mutations in Japanese colorectal cancer patients. Shao R. X., Kato N., Lin L. J., Muroyama R., Moriyama M., Ikenoue T., Watabe H., Otsuka M., Guleng B., Ohta M., Tanaka Y., Kondo S., Dharel N., Chang J. H., Yoshida H., Kawabe T., Omata M. Oncogene. 2006; (Epub ahead of print). Medline 17016444

Mutations in HOXD13 Underlie Syndactyly Type V and a Novel Brachydactyly-Syndactyly Syndrome. Zhao X, Sun M, Zhao J, Leyva JA, Zhu H, Yang W, Zeng X, Ao Y, Liu Q, Liu G, Lo WH, Jabs EW, Amzel LM, Shan X, Zhang X. Am J Hum Genet. 2007; 80(2): 361-371. Medline 17236141

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 2-2007 Haruhiko Sugimura, Hiroki Mori, Tomoyasu Bunai, Masaya Suzuki Citation This paper should be referenced as such : Sugimura H, Mori H, Bunai T, Suzuki M . EPHA7 (EPH receptor A7). Atlas Genet Cytogenet Oncol Haematol. . URL : http://AtlasGeneticsOncology.org/Genes/EPHA7ID40466ch6q16.html

Atlas Genet Cytogenet Oncol Haematol 2007; 3 311 © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 312 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RNASET2 (ribonuclease T2)

Identity Other names RNASE6PL RP11-514O12.3 bA514O12.3 Hugo RNASET2 Location 6q27 Local_order Telomeric to RPS6KA2, centromeric to FGFR1OP. Note This gene is the first human member of the Rh/T2/S-glycoprotein family of extracellular ribonucleases. It is a putative class II tumor suppressor gene potentially involved in the pathogenesis of several solid and haematologic human neoplasias such as ovarian cancer, melanoma and non-Hodgkin lymphoma. DNA/RNA

I-IX: RNASET2 exons.

Description This gene is split in 9 exons spanning approximatly 27 kb of genomic DNA. The translation initiation codon is located to exon 1 and the stop codon to exon 9. Exons III and VI encode the two CAS motifs (Catalytic Active Sites) responsible for the ribonuclease activity of the RNASET2 protein. Transcriptio The RNASET2 gene is transcribed in the telomere-to-centromere orientation to produce n an ubiquitously expressed mRNA approximately 1,4 kb in length. EST clones representing splice variants of the same gene have been described. Pseudogene A processed pseudogene showing 85% identity with RNASET2 mRNA maps to chromosome 7p11.2. The expression pattern of this pseudogene is not known. Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 3 313

Description The full-length RNASET2 protein contains 256 aminoacids and displays an apparent MW of 36 kDa in its secreted form. Two 31 and 27 kDa C-terminal proteolytic products have also been observed intracellularly in several human cancer cell lines and localize to the lysosome. Expression Expression of the RNASET2 protein has been detected in several human ovarian cancer cell lines and in some melanoma, prostate, pancreatic and breast carcinoma cell lines. Localisation The RNASET2 protein can be detected either intracellularly within lysosomes and secretory pathway, or extracellularly in a secreted form (in cell culture supernatants). Function Biochemical function : RNASET2 is an acid ribonuclease with optimal activity at pH 5 and preferential cleavage of poly-A and poly-U homo-polyribonucleotides. Biological function : RNASET2 behaves as a class II tumor suppressor gene for ovarian cancer, since experimental overexpression of this gene in human ovarian cancer cell lines is associated with a significant decrease of their tumorigenic and metastasizing potential in vivo. Strikingly, the ribonuclease catalytic activity is apparently dispensable for RNASET2 to play such antioncogenic role. Indeed, a double CAS mutant cDNA construct encoding an almost inactive RNASET2 protein is still able to suppress tumorigenicity and metastasis when overexpressed in the same ovarian cancer cell lines. Such results have been recently confirmed in a human melanoma cell line. Homology The primary sequenze of RNASET2 shows strong homology to the Rh/T2/S family of secreted ribonucleases. Mutations Germinal A common exon-9 missense C708T germline mutation has been described but no evidence for an association of this allele with human cancer was found. Somatic A few common polymorphisms in exons 1, 8 and 9 have been described. Implicated in Entity Human ovarian carcinoma. Disease Loss of expression of RNASET2 occurs in a significant fraction of human ovarian cancer cell lines and primary ovarian tumours. When overexpressed by gene transfer experiments in human ovarian cancer cell lines displaying a low level of endogenous mRNA, RNASET2 strongly suppresses the tumorigenic and metastatic potential of these cell lines in vivo. Cytogenetics The RNASET2 genes maps in a genomic region (6q27) which is frequently deleted or otherwise rearranged in a wide range of human neoplasias, including ovarian cancer. External links Nomenclature

Atlas Genet Cytogenet Oncol Haematol 2007; 3 314 Hugo RNASET2 GDB RNASET2 Entrez_Gene RNASET2 8635 ribonuclease T2 Cards Atlas RNASET2ID518ch6q27 GeneCards RNASET2 Ensembl RNASET2 Genatlas RNASET2 GeneLynx RNASET2 eGenome RNASET2 euGene 8635 Genomic and cartography GoldenPath RNASET2 - 6q27 chr6:167263003-167290067 - 6q27 (hg18-Mar_2006) Ensembl RNASET2 - 6q27 [CytoView] NCBI Mapview HomoloGene RNASET2 Gene and transcription Genbank AJ419865 [ ENTREZ ] Genbank AJ419866 [ ENTREZ ] Genbank AJ419867 [ ENTREZ ] Genbank AK000385 [ ENTREZ ] Genbank AK001769 [ ENTREZ ] RefSeq NM_003730 [ SRS ] NM_003730 [ ENTREZ ] RefSeq AC_000049 [ SRS ] AC_000049 [ ENTREZ ] RefSeq NC_000006 [ SRS ] NC_000006 [ ENTREZ ] RefSeq NT_007422 [ SRS ] NT_007422 [ ENTREZ ] RefSeq NW_923184 [ SRS ] NW_923184 [ ENTREZ ] AceView RNASET2 AceView - NCBI Unigene Hs.529989 [ SRS ] Hs.529989 [ NCBI ] HS529989 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O00584 [ SRS] O00584 [ EXPASY ] O00584 [ INTERPRO ] Prosite PS00530 RNASE_T2_1 [ SRS ] PS00530 RNASE_T2_1 [ Expasy ] Prosite PS00531 RNASE_T2_2 [ SRS ] PS00531 RNASE_T2_2 [ Expasy ] Interpro IPR001568 RNase_T2 [ SRS ] IPR001568 RNase_T2 [ EBI ] CluSTr O00584 PF00445 Ribonuclease_T2 [ SRS ] PF00445 Ribonuclease_T2 [ Sanger Pfam ] pfam00445 [ NCBI-CDD ] Blocks O00584 HPRD O00584 Protein Interaction databases DIP O00584 IntAct O00584 Polymorphism : SNP, mutations, diseases SNP RNASET2 [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 315 SNP NM_003730 [SNP-NCI] SNP RNASET2 [GeneSNPs - Utah] RNASET2] [HGBASE - SRS] HAPMAP RNASET2 [HAPMAP] General knowledge Family RNASET2 [UCSC Family Browser] Browser SOURCE NM_003730 SMD Hs.529989 SAGE Hs.529989 Enzyme 3.1.27.- [ Enzyme-SRS ] 3.1.27.- [ Brenda-SRS ] 3.1.27.- [ KEGG ] 3.1.27.- [ WIT ] GO RNA binding [Amigo] RNA binding GO endoribonuclease activity [Amigo] endoribonuclease activity GO extracellular region [Amigo] extracellular region GO RNA catabolic process [Amigo] RNA catabolic process GO activity [Amigo] hydrolase activity PubGene RNASET2 Other databases Probes Probe RNASET2 Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography Mammalian Rh/T2/S-glycoprotein ribonuclease family genes: cloning of a human member located in a region of (6q27) frequently deleted in human malignancies. Trubia M, Sessa L, Taramelli R. Genomics. 1997;42:342-344. Medline 9192857

Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27. Acquati F, Morelli C, Cinquetti R, Bianchi MG, Porrini D, Varesco L, Gismondi V, Rocchetti R, Talevi S, Possati L, Magnanini C, Tibiletti MG, Bernasconi B, Daidone MG, Shridhar V, Smith DI, Negrini M, Barbanti-Brodano G, Taramelli R. Oncogene. 2001;20:980-988. Medline 11314033

Molecular cloning, tissue distribution, and chromosomal localization of the human homolog of the R2/Th/Stylar ribonuclease gene family. Acquati F, Nucci C, Bianchi MG, Gorletta T, Taramelli R. Methods Mol Biol. 2001;160:87-101. Medline 11265308

Tumor and metastasis suppression by the human RNASET2 gene. Acquati F, Possati L, Ferrante L, Campomenosi P, Talevi S, Bardelli S, Margiotta C, Russo A, Bortoletto E, Rocchetti R, Calza R, Cinquetti R, Monti L, Salis S, Barbanti-Brodano G, Taramelli R. Int J Oncol. 2005; 26:1159-1168. Medline 15809705

Characterization of RNASET2, the first human member of the Rh/T2/S family of glycoproteins.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 316 Campomenosi P, Salis S, Lindqvist C, Mariani D, Nordstrom T, Acquati F, Taramelli R. Arch Biochem Biophys. 2006;449:17-26. Medline 16620762

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Francesco Acquati, Paola Campomenosi Citation This paper should be referenced as such : Acquati F, Campomenosi P . RNASET2 (ribonuclease T2). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RNASET2ID518ch6q27.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 317 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RHOB (ras homolog gene family, member B)

Identity Other names ARH6 ARHB H6 RHOH6 Hugo RHOB Location 2p24.1 DNA/RNA

Description The gene encompasses 2,366 bps (chr2:20,510,316-20,512,681); 1 exon. Transcription The coding sequence (CDS) region is 395.983bp (588 bp) encoding a protein of 196 aa long. Protein

Description Length 196 aa, molecular weight 22123 Da (unprocessed precursor). RhoB protein exists in different geranylgeranylated (RhoB-GG) or farnesylated (RhoB-F) isoforms in cells. Expression Widely expressed. Localisation Endosome; Late endosome; late endosomal membrane; cell membrane; Also detected at the nuclear margin and in the nucleus. Prenylation specifies the subcellular location of RHOB. In general, the farnesylated form is localized to the plasma membrane while the geranylgeranylated form is localized to the endosome. Function Regulator of protein signaling and trafficking: Plays a pivotal role in the dynamic regulation of the cytoskeleton. Involved in intracellular protein trafficking of a number of proteins. Targets PRK1 to endosomes and is involved in trafficking of the EGF receptor from late endosomes to lysosomes. Also required for stability and nuclear trafficking of Akt which promotes endothelial cell survival during vascular development. Identified as a component of outside-in signaling pathways that coordinate Src activation with its translocation to transmembrane receptors. Negative modifier of cancer progression: Affects cell adhesion and growth factor signaling in transformed cells. Plays a negative role in tumorigenesis as RhoB deletion increases tumor formation initiated by Ras mutation. Limits the proliferation of transformed cells by facilitating turnover of oncogene c-Myc. Expression levels are dramatically decreased in lung, head and neck, and brain cancer, when tumors become more aggressive. Modulator of cancer cell apoptosis:

Atlas Genet Cytogenet Oncol Haematol 2007; 3 318 Promotes proapoptotic signaling of regulators involved in cell cycle checkpoints, cell adhesion, vesicle trafficking, MAPK signaling, transcription, and immunity. Mediates apoptosis in neoplastically transformed cells after DNA damage. Is essential for apoptosis and antineoplastic activity of farnesyltransferase inhibitors in a mouse model. Is one of the targets of farnesyltransferase inhibitors which are currently under investigation as cancer therapeutics. Homology Member of the ras gene superfamily; rho family; GTP-binding proteins. The RhoA, RhoB, and RhoC proteins form a closely related subgroup that are about 90% identical in amino acid sequence. The sequences of RHOB are highly-conserved between species (from human to fly). Amino acid sequences of human, mouse and rat are 100% identical while between human and chicken is 97% identical. Implicated in Entity Lung cancer Note RhoB expression is frequently downregulated in lung cancer by multiple mechanisms. Low or no expression of RhoB is more frequently observed in poorly- or moderately- differentiated adenocarcinomas, and indicative of poor patient prognosis.

Entity Head and neck cancer Note RhoB expression decreases to undetectable level as tumors become more invasive and poorly differentiated. In contrast, Ki67 (proliferation marker) and RhoA protein levels increase with tumor progression.

External links Nomenclature Hugo RHOB GDB RHOB Entrez_Gene RHOB 388 ras homolog gene family, member B Cards Atlas RHOBID42108ch2p24 GeneCards RHOB Ensembl RHOB Genatlas RHOB GeneLynx RHOB eGenome RHOB euGene 388 Genomic and cartography GoldenPath RHOB - 2p24.1 chr2:20510316-20512681 + 2p24 (hg18-Mar_2006) Ensembl RHOB - 2p24 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene RHOB Gene and transcription Genbank AF171089 [ ENTREZ ] Genbank AF498971 [ ENTREZ ] Genbank AK124398 [ ENTREZ ] Genbank BC062781 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 319 Genbank BC066954 [ ENTREZ ] RefSeq NM_004040 [ SRS ] NM_004040 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ] RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_015926 [ SRS ] NT_015926 [ ENTREZ ] RefSeq NW_927719 [ SRS ] NW_927719 [ ENTREZ ] AceView RHOB AceView - NCBI Unigene Hs.502876 [ SRS ] Hs.502876 [ NCBI ] HS502876 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P62745 [ SRS] P62745 [ EXPASY ] P62745 [ INTERPRO ] Interpro IPR003578 GTPase_Rho [ SRS ] IPR003578 GTPase_Rho [ EBI ] Interpro IPR013753 Ras [ SRS ] IPR013753 Ras [ EBI ] Interpro IPR001806 Ras_trnsfrmng [ SRS ] IPR001806 Ras_trnsfrmng [ EBI ] Interpro IPR005225 Small_GTP_bd [ SRS ] IPR005225 Small_GTP_bd [ EBI ] CluSTr P62745 Pfam PF00071 Ras [ SRS ] PF00071 Ras [ Sanger ] pfam00071 [ NCBI-CDD ] Smart SM00174 RHO [EMBL] Blocks P62745 PDB 2FV8 [ SRS ] 2FV8 [ PdbSum ], 2FV8 [ IMB ] 2FV8 [ RSDB ] HPRD P62745 Protein Interaction databases DIP P62745 IntAct P62745 Polymorphism : SNP, mutations, diseases OMIM 165370 [ map ] GENECLINICS 165370 SNP RHOB [dbSNP-NCBI] SNP NM_004040 [SNP-NCI] SNP RHOB [GeneSNPs - Utah] RHOB] [HGBASE - SRS] HAPMAP RHOB [HAPMAP] General knowledge Family RHOB [UCSC Family Browser] Browser SOURCE NM_004040 SMD Hs.502876 SAGE Hs.502876 GO nucleotide binding [Amigo] nucleotide binding GO angiogenesis [Amigo] angiogenesis GO GTPase activity [Amigo] GTPase activity GO protein binding [Amigo] protein binding GO GTP binding [Amigo] GTP binding GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO plasma membrane [Amigo] plasma membrane

Atlas Genet Cytogenet Oncol Haematol 2007; 3 320 GO transformed cell apoptosis [Amigo] transformed cell apoptosis GO cell cycle [Amigo] cell cycle GO cell adhesion [Amigo] cell adhesion small GTPase mediated signal transduction [Amigo] small GTPase mediated signal GO transduction GO Rho protein signal transduction [Amigo] Rho protein signal transduction GO multicellular organismal development [Amigo] multicellular organismal development GO endosome to lysosome transport [Amigo] endosome to lysosome transport GO endosome membrane [Amigo] endosome membrane GO protein transport [Amigo] protein transport GO cell differentiation [Amigo] cell differentiation GO positive regulation of angiogenesis [Amigo] positive regulation of angiogenesis negative regulation of progression through cell cycle [Amigo] negative regulation of GO progression through cell cycle PubGene RHOB Other databases Probes Probe RHOB Related clones (RZPD - Berlin) PubMed PubMed 47 Pubmed reference(s) in LocusLink Bibliography A novel ras-related gene family. Madaule P, Axel R. Cell. 1985; 41(1): 31-40. Medline 3888408

Coding sequence of human rho cDNAs clone 6 and clone 9. Chardin P, Madaule P, Tavitian A. Nucleic Acids Res. 1988; 25;16(6): 2717. Medline 3283705

Chromosome localization of human ARH genes, a ras-related gene family. Cannizzaro LA, Madaule P, Hecht F, Axel R, Croce CM, Huebner K. Genomics. 1990; 6(2): 197-203. Medline 2407642

Post-translational modifications of p21rho proteins. Adamson P, Marshall CJ, Hall A, Tilbrook PA. J Biol Chem. 1992; 267(28): 20033-20038. Medline 1400319

CAAX geranylgeranyl transferase transfers farnesyl as efficiently as geranylgeranyl to RhoB. Armstrong SA, Hannah VC, Goldstein JL, Brown MS. J Biol Chem. 1995; 270(14): 7864-7868. Medline 7713879

Regulation of epidermal growth factor receptor traffic by the small GTPase rhoB. Gampel A, Parker PJ, Mellor H. Curr Biol. 1999; 9(17): 955-958.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 321 Medline 10508588

RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Liu A, Du W, Liu JP, Jessell TM, Prendergast GC. Mol Cell Biol. 2000; 20(16): 6105-6113. Medline 10913192

RhoB is required to mediate apoptosis in neoplastically transformed cells after DNA damage. Liu Ax, Cerniglia GJ, Bernhard EJ, Prendergast GC. Proc Natl Acad Sci U S A. 2001; 98(11): 6192-6197. Medline 11353846

Actin' up: RhoB in cancer and apoptosis. Prendergast GC. Nat Rev Cancer. 2001; 1(2): 162-168. Review. Medline 11905808

Suppression of rho B expression in invasive carcinoma from head and neck cancer patients. Adnane J, Muro-Cacho C, Mathews L, Sebti SM, Munoz-Antonia T. Clin Cancer Res. 2002; 8(7): 2225-2232. Medline 12114424

RhoB controls Akt trafficking and stage-specific survival of endothelial cells during vascular development. Adini I, Rabinovitz I, Sun JF, Prendergast GC, Benjamin LE. Genes Dev. 2003; 17(21): 2721-2732. Medline 14597666

EGFR, ErbB2 and Ras but not Src suppress RhoB expression while ectopic expression of RhoB antagonizes oncogene-mediated transformation. Jiang K, Delarue FL, Sebti SM. Oncogene. 2004; 23(5): 1136-1145. Medline 14647415

Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Jiang K, Sun J, Cheng J, Djeu JY, Wei S, Sebti S. Mol Cell Biol. 2004; 24(12): 5565-5576. Medline 15169915

Farnesyltransferase inhibitors disrupt EGF receptor traffic through modulation of the RhoB GTPase. Wherlock M, Gampel A, Futter C, Mellor H. J Cell Sci. 2004; 117(Pt 15): 3221-3231. Medline 15226397

Loss of RhoB expression in human lung cancer progression. Mazieres J, Antonia T, Daste G, Muro-Cacho C, Berchery D, Tillement V, Pradines A, Sebti S, Favre G. Clin Cancer Res. 2004; 10(8): 2742-2750. Medline 15102679

RhoB and actin polymerization coordinate Src activation with endosome-mediated delivery to

Atlas Genet Cytogenet Oncol Haematol 2007; 3 322 the membrane. Sandilands E, Cans C, Fincham VJ, Brunton VG, Mellor H, Prendergast GC, Norman JC, Superti- Furga G, Frame MC. Dev Cell. 2004; 7(6): 855-869. Medline 15572128

RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3. Huang M, Kamasani U, Prendergast GC. Oncogene. 2006; 25(9): 1281-1289. Medline 16247449

RhoB in cancer suppression. Huang M, Prendergast GC. Histol Histopathol. 2006; 21(2): 213-218. Review. Medline 16329046

RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line. ISato N, Fukui T, Taniguchi T, Yokoyama T, Kondo M, Nagasaka T, Goto Y, Gao W, Ueda Y, Yokoi K, Minna JD, Osada H, Kondo Y, Sekido Y. Int J Cancer. 2006; [Epub ahead of print] Medline 17096327

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Minzhou Huang, Lisa D Laury-Kleintop, George Prendergast Citation This paper should be referenced as such : Huang M, Laury-Kleintop LD, Prendergast G . RHOB (ras homolog gene family, member B). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RHOBID42108ch2p24.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 323 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RBM5 (RNA binding motif protein 5)

Identity Other names LUCA-15 H37 G15 Hugo RBM5 Location 3p21.3 Note 3p21.3 is a putative human lung cancer tumor suppressor region. RBM5/LUCA-15 is a putative tumor suppressor gene DNA/RNA

RBM5/LUCA-15 splice variants. Boxes represent the exons, intronic sequences are represented by horizontal lines. The arrows point to the STOP codon in the protein coding sequence.

Description The gene spans about 30.03 Kb. Orientation plus strand. At least 25 exons. Transcription Full length RBM5 has 3.1 Kb, 2448 bp open reading frame. The gene encodes a number of alternative splice variants, identified by reverse transcription polymerase chain reaction. One splice variant lacks exon 6, RBM5delta6. Three other RNA splice variants retain intronic sequences, RBM5+5+6 retains introns 5 and 6, RBM5+6 retains intron 6 and clone 26 which is a partial cDNA containing an open reading frame and terminates within intron 6. A 326 bp antisense cDNA that maps to the intronic region of RBM5, je2, has also been identified. Both, RBM5delta6 and clone 26 cDNAs have been cloned. Protein Description Full length RBM5 encodes a protein with a molecular mass of about 90 kDa (815 amino acids). The protein has two RNA Binding Domains (RBD), also recognized as RNA Recognition Motif (RRM). RBM5 structure also features other functional motifs, which includes two putative zinc-finger DNA binding motifs, two bipartite nuclear localisation signals and a G-patch domain (a conserved domain in eukaryotic RNA- processing proteins and type D retroviral polyproteins), suggesting a role for RBM5/LUCA-15 in RNA processing. In addition, the C-terminal region of RBM5/LUCA- 15 contains several domains including a glutamine rich domain (362-385), which is thought to serve as protein-protein interaction site in certain RNA- and DNA- binding

Atlas Genet Cytogenet Oncol Haematol 2007; 3 324 proteins. RBM5delta6 encodes a protein of 17 kDa, due to a frameshift mutation caused by the deletion of exon 6. The only functional motif retained by this truncated protein is the arginine/glycine-rich amino terminal region. A putative 21 kDa is reported to be encoded by RBM5+5+6 and clone 26, as revealed by an in vitro transcription/translation study in rabbit reticulocyte lysate. Expression Full length RBM5 and its alternative splice variants RNA are widely expressed in both primary tissue and cell lines. Northern blot analysis revealed higher expression in skeletal and heart muscles and pancreas. The expression of the full length RBM5 mRNA is reported to be high in adult thymus and low in the foetal thymus, suggesting that its expression is developmentally regulated. Full length RBM5/LUCA-15 is reported to be down-regulated in breast cancer specimens, in 82% of primary non- small-cell lung carcinoma specimens and in many lung cancer cell lines and in vestibular schwannomas (27 fold reduction). The expression of RBM5delta6 RNA is highest in transformed cells. The full length RBM5 protein is ubiquitously expressed in human tissues. It was found to be downregulated in 73% of primary non-small-cell lung carcinoma specimens compared to normal adjacent tissue. RBM5/LUCA-15 was one of the antigens identified by autologous antibody in patients with renal carcinoma. Overexpression of je2, the 326 bp antisense sequence, resulted in the downregulation of the RBM5 protein (95 kDa) and the upregulation of the 17 kDa protein (RBM5delta6). Localisation RBM5 protein includes bipartite nuclear localisation signals suggesting its localisation to the nucleus. Function RBM5/LUCA-15 is among the 35 genes located within the 370 kb overlapping lung cancer homozygous deletion region at 3p21.3. RBM5 has been implicated in the control of cell death by apoptosis and cell proliferation. RBM5's involvement in apoptosis and malignancy has been the focus of many recent studies, with all results converging on a role for RBM5/LUCA-15 as a Tumor Suppressor Gene (TSG). RBM5 splice variants have been shown to function as regulators of apoptosis. Stable expression of Je2, in human T-cell lines CEM-C7 and Jurkat produced marked inhibition of Fas-mediated apoptosis and conferred protection from apoptosis induced by other stimuli. RBM5delta6 inhibits CD95-mediated apoptosis as well as accelerating cell proliferation. Overexpression of the full length RBM5 in CEM-C7 and Jurkat T-cell lines suppressed cell proliferation both by inducing apoptosis and by inducing cell cycle arrest in G1. Consistently, RBM5/LUCA-15 overexpression also inhibited human lung cancer cell growth (A549 non-small cell lung cancer line) by increasing apoptosis and inducing cell cycle arrest in G1. This inhibition of cell growth was reported to be associated with decreased cyclin A and phosphorylated RB and an increase in the level of the proapototic protein Bax. Introducing RBM5/LUCA-15 into breast cancer cells that had 3p21-22 deletions reduced both anchorage-dependent and anchorage-independent growth. RBM5/LUCA-15 also is reported to suppress anchorage-dependent and anchorage-independent growth in A9 mouse fibrosarcoma cells and to inhibit their tumour forming activity in nude mice. RBM5/LUCA-15 was one of the nine genes down-regulated in metastasis and it has been included in the 17 common gene signature associated with metastasis identified in multiple solid tumour types. Solid tumours carrying this gene expression signature had high rates of metastasis and poor clinical outcome. Microarray-based analysis of changes in gene expression caused by the modulation of the level of RBM5/LUCA-15 were carried out. Among 5603 genes on cDNA microarray, 35 genes, well known for their roles in the cell cycle as well as in apoptosis, were found to be differentially expressed as a result of RBM5/LUCA-15 overexpression in CEM-C7 cells. These RBM5/LUCA-15 modulated genes include a number of cyclin-dependent kinase complexes, most notably CDK2 and three putative oncogenes which are down- regulated by RBM5/LUCA-15. These are Pim-1, a serine/threonine kinase, ITPA (inosine triphosphate pyrophosphatase) and Amplified in Breast cancer 1 (AIB1). Other functionally important genes modulated by RBM5/LUCA-15 are well established to play specific anti apoptotic roles such as BIRC4 (AIP3), BIRC3 (cIAP2, MIHC), Mcl- 1, a member of the Bcl-2 family of apoptosis suppressors, and TRAF1, supporting a

Atlas Genet Cytogenet Oncol Haematol 2007; 3 325 role for RBM5/LUCA-15 in apoptosis. Other genes upregulated by RBM5/LUCA-15 include Stat5b, Annexin I and Bone Morphogenetic Protein 5 (BMP5), implicated in apoptosis, immunosuppression and organ development respectively. Homology RBM5 shares 30% amino acid sequence homology with its immediate telomeric neighbor, the putative tumor suppressor gene RBM6. Another RNA Binding Motif protein that shares high homology with RBM5 (53% at the amino acid level) is RBM10. The RBM10 gene is located on the at p11.23. No function has yet been determined for RBM10. The mouse RBM5 gene is 90% identical on cDNA level and 97% on protein level. The fly proteome contain three similar proteins, of which CG4887 gene product shows 43% similarity. The rat binding protein S1-1 has similar domain structure and is close in amino acid sequence to RBM5. Mutations Note Mutations in the RMB5 gene have not been found in lung cancer. RBM5 is reported to be downregulated in RAS-transformed Rat-1 cells, in samples from breast cancer, in human schwannomas and in about 75% of primary lung cancers specimens. RBM5 was one of the nine genes down-regulated in metastasis in primary tumors and it has been included in the 17 common gene signature associated with metastasis identified in multiple solid tumour types. Solid tumours carrying this gene expression signature had high rates of metastasis and poor clinical outcomes. Implicated in Entity Lung cancer and many other cancers Disease RBM5 is located at the human chromosomal 3p21.3, which is strongly associated with lung cancer and many other cancers, including head and neck, renal, breast and female genital tract. More than 90% of freshly microdissected primary lung cancers display loss of heterozygosity (LOH) of 3p21.3. RBM5 is implicated in apoptosis and in cell cycle regulation. Oncogenesis The ability of RBM5/LUCA-15 to inhibit the growth of transformed cells fulfils one of the criteria for a tumor suppressor. The simultaneous changes in proliferation and inhibition of apoptosis brought about by dysregulation of the RBM5/LUCA-15 locus are likely to be of major significance in oncogenesis.

External links Nomenclature Hugo RBM5 GDB RBM5 Entrez_Gene RBM5 10181 RNA binding motif protein 5 Cards Atlas RBM5ID42069ch3p21 GeneCards RBM5 Ensembl RBM5 Genatlas RBM5 GeneLynx RBM5 eGenome RBM5 euGene 10181 Genomic and cartography GoldenPath RBM5 - 3p21.3 chr3:50101372-50131394 + 3p21.3 (hg18-Mar_2006) Ensembl RBM5 - 3p21.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 326 HomoloGene RBM5 Gene and transcription Genbank AB208813 [ ENTREZ ] Genbank AF091263 [ ENTREZ ] Genbank AF103802 [ ENTREZ ] Genbank AF107493 [ ENTREZ ] Genbank AK097195 [ ENTREZ ] RefSeq NM_005778 [ SRS ] NM_005778 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_022517 [ SRS ] NT_022517 [ ENTREZ ] RefSeq NW_921651 [ SRS ] NW_921651 [ ENTREZ ] AceView RBM5 AceView - NCBI Unigene Hs.439480 [ SRS ] Hs.439480 [ NCBI ] HS439480 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P52756 [ SRS] P52756 [ EXPASY ] P52756 [ INTERPRO ] Prosite PS50174 G_PATCH [ SRS ] PS50174 G_PATCH [ Expasy ] Prosite PS50102 RRM [ SRS ] PS50102 RRM [ Expasy ] Prosite PS01358 ZF_RANBP2_1 [ SRS ] PS01358 ZF_RANBP2_1 [ Expasy ] Prosite PS50199 ZF_RANBP2_2 [ SRS ] PS50199 ZF_RANBP2_2 [ Expasy ] PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 ZINC_FINGER_C2H2_1 [ Prosite Expasy ] PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 ZINC_FINGER_C2H2_2 [ Prosite Expasy ] Interpro IPR012677 a_b_plait_nuc_bd [ SRS ] IPR012677 a_b_plait_nuc_bd [ EBI ] Interpro IPR000467 G_patch [ SRS ] IPR000467 G_patch [ EBI ] Interpro IPR000504 RNP1_RNA_bd [ SRS ] IPR000504 RNP1_RNA_bd [ EBI ] Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] Interpro IPR001876 Znf_RanBP2 [ SRS ] IPR001876 Znf_RanBP2 [ EBI ] CluSTr P52756 Pfam PF01585 G-patch [ SRS ] PF01585 G-patch [ Sanger ] pfam01585 [ NCBI-CDD ] Pfam PF00076 RRM_1 [ SRS ] PF00076 RRM_1 [ Sanger ] pfam00076 [ NCBI-CDD ] PF00641 zf-RanBP [ SRS ] PF00641 zf-RanBP [ Sanger ] pfam00641 [ NCBI- Pfam CDD ] Smart SM00443 G_patch [EMBL] Smart SM00360 RRM [EMBL] Smart SM00355 ZnF_C2H2 [EMBL] Smart SM00547 ZnF_RBZ [EMBL] Blocks P52756 HPRD P52756 Protein Interaction databases DIP P52756 IntAct P52756 Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 2007; 3 327 OMIM 606884 [ map ] GENECLINICS 606884 SNP RBM5 [dbSNP-NCBI] SNP NM_005778 [SNP-NCI] SNP RBM5 [GeneSNPs - Utah] RBM5] [HGBASE - SRS] HAPMAP RBM5 [HAPMAP] General knowledge Family RBM5 [UCSC Family Browser] Browser SOURCE NM_005778 SMD Hs.439480 SAGE Hs.439480 GO nucleotide binding [Amigo] nucleotide binding GO DNA binding [Amigo] DNA binding GO RNA binding [Amigo] RNA binding GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO RNA processing [Amigo] RNA processing GO cell cycle [Amigo] cell cycle GO zinc ion binding [Amigo] zinc ion binding negative regulation of progression through cell cycle [Amigo] negative regulation of GO progression through cell cycle GO metal ion binding [Amigo] metal ion binding PubGene RBM5 Other databases Probes Probe RBM5 Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography A homozygous deletion on in a small cell lung cancer cell line correlates with a region of tumour suppressor activity. Daly MC, Xiang RH, Buchhagen D, Hensel CH, Garcia DK, Killary AM, Minna JD, Naylor SL. Oncogene. 1993; 8: 1721-1729. Medline 8390035

Conserved structures and diversity of functions of RNA-binding proteins. Burd C.G. and Dreyfuss G. Science. 1994; 265(5172): 615-621. Medline 8036511

A group of NotI jumping and linking clones cover 2.5 Mb in the 3p21-p22 region suspected to contain a tumour suppressor gene. Kashuba VI, Szeles A, Allikmets R, Nilsson AS, Bergerheim US, Modi W, Grafodatsky A, Dean M, Stanbridge EJ, Winberg G, klein G., Zabarovsky E.R., and Kisselev L. Cancer Genet Cytogenet. 1995; 81(2): 144-150.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 328 Medline 7621411

Molecular cloning of a candidate tumour suppressor gene, DLC1, from chromosome 3p21.3. Daigo Y., Nishiwaki T., Kawasoe T., Tamari M., Suchiya E., and Nakamura Y. Cancer Res. 1996; 59: 1966-1972. Medline 10072596

Construction of a 600-kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumour suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG. Wei MH, Latif F, Bader S, Kashuba V, Chen JY, Duh FM, Sekido Y, Lee C.C, Geil L, Kuzmin I, Zabarovsky E, Klein G, Zbar B, Minna JD, and Lerman MI. Cancer Res. 1996; 56: 1487-1492. Medline 8603390

Differential elimination of 3p and retention of 3q segments in human/mouse microcell hybrids during tumour growth. Imreh S, Kost-Alimova M, Kholodnyuk I, Yang Y,Szeles A, Kiss H, Liu F, Foster K, Zabarovsky E, Stanbridge E, and Klein G. Genes Chrom. Cancer. 1997; 20: 224-233. Medline 9365829

Deletion of the short arm of chromosome 3 in solid tumours and the search for suppressor genes. Kok K, Naylor SL, Buys CH. Adv Cancer Res. 1997; 71: 27-92. Medline 9111863

Human lung cancer antigens recognized by autologous antibodies: definition of a novel cDNA derived from the tumour suppressor gene locus on chromosome 3p21.3. Gure AO, Altorki NK, Stockert E, Scanlan MJ, Old LJ, Chen YT. Cancer Res. 1998; 58(5): 1034-1041. Medline 9500467

G-patch: a new conserved domain in eukaryotic RNA-processing proteins and type D retroviral polyproteins. Aravind L and Koonin EV. Trends Biochem. Sci. 1999; 24: 342-344. Medline 10470032

DEF-3(g16/NY-LU-12), an RNA binding protein from the 3p21.3 homozygous deletion region in SCLC. Drabkin HA, West JD, Hotfilder M, Heng YM, Erickson P, Calvo R, Dalmau J, Gemmill RM, Sablitzky F. Oncogene. 1999; 18(16): 2589-2597. Medline 10353602

Def-2, -3, -6 and -8, novel mouse genes differentially expressed in the haemopoietic system. Hotfilder M, Baxendale S, Cross MA, and Sablitzky F. Br. J. Haematol. 1999; 106: 335-344. Medline 10460589

Antigens recognized by autologous antibody in patients with renal-cell carcinoma. Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jager D, Jager E, Knuth A, Chen YT, Old LJ.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 329 Int J Cancer. 1999; 83(4): 456-464. Medline 10508479

A comparison of genomic structures and expression patterns of two closely related flanking genes in a critical lung cancer region at 3p21.3. Timmer T, Terpstra P, van den Berg A, Veldhuis PM, Ter Elst A, Voutsinas G, Hulsbeek MM, Draaijers TG, Looman MW, Kok K, Naylor SL, Buys CH. Eur J Hum Genet. 1999; 7(4): 478-486. Medline 10352938

LUCA15, a putative tumour suppressor gene encoding an RNA-binding nuclear protein, is down-regulated in ras-transformed Rat-1 cells. Edamatsu H, Kaziro Y, Itoh H. Genes Cells. 2000; 5: 849-858. Medline 11029660

The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumour suppressor genes. Lerman MI, Minna JD. Cancer Res. 2000; 60: 6116-6133. Medline 11085536

LUCA-15-encoded sequence variants regulate CD95-mediated apoptosis. Sutherland LC, Edwards SE, Cable HC, Poirier GG, Miller BA, Cooper CS, Williams GT. Oncogene. 2000; 19(33): 3774-3781. Medline 10949932

Candidate tumour suppressor LUCA-15 can regulate multiple apoptosis pathways. Mourtada-Maarabouni M, Sutherland LC, Williams GT. Apoptosis. 2002; 7: 421-432. Medline 12207175

RBM5/LUCA-15--tumour suppression by control of apoptosis and the cell cycle? Mourtada-Maarabouni M and Willimas GT. ScientificWorldJournal. 2002; 4(2): 1885-1890.( Review) Medline 12920317

A candidate tumour suppressor gene, H37, from the human lung cancer tumour suppressor locus 3p21.3. Oh JJ, West AR, Fishbein MC, Slamon DJ. Cancer Res. 2002; 62(11): 3207-3213. Medline 12036935 cDNA microarray analysis of vestibular schwannomas. Welling DB, Lasak JM, Akhmametyeva E, Ghaheri B, Chang LS. Otol Neurotol. 2002; 23(5): 736-748. Medline 12218628

Splice variant delta 6 of the candidate tumor suppressor LUCA-15/RBM5 both stimulates cell proliferation and suppresses apoptosis. Mourtada-Maarabouni M, Sutherland LC, Meredith JM, Williams GT. Genes Cells. 2003; 8(2): 109-119. Medline 12581154

Atlas Genet Cytogenet Oncol Haematol 2007; 3 330 A molecular signature of metastasis in primary solid tumours. Ramaswamy S, Ross KN, Lander ES, Golub TR. Nat Genet. 2003; 33(1): 49-53. Medline 12469122

RNA Binding Motif (RBM) proteins: A novel family of apoptosis modulators? Sutherland LC, Rintala-Maki ND, White RD, Morin CD. J Cell Biochem. 2005; 94(1): 5-24. (Review) Medline 15514923

Candidate tumor suppressor LUCA-15/RBM5/H37 modulates expression of apoptosis and cell cycle genes. Mourtada-Maarabouni M, Keen J, Clark J, Cooper CS, Williams GT. Exp Cell Res. 2006; 312(10): 1745-1752. Medline 16546166

The antiapoptotic RBM5/LUCA-15/H37 gene and its role in apoptosis and human cancer research update. Maarabouni MM, Williams GT. ScientificWorldJournal. 2006; 6: 1705-1712.( Review) Medline 17195868

3p21.3 Tumour suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. Oh JJ, Razfar A, Delgado I, Reed RA, Malkina A, Boctor B, Slamon DJ. Cancer Res. 2006; 66(7): 3419-3427. Medline 16585163

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Mirna Mourtada-Maarabouni Citation This paper should be referenced as such : Mourtada-Maarabouni M . RBM5 (RNA binding motif protein 5). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RBM5ID42069ch3p21.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 331 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RAC3 (ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3)) Identity Other names - Hugo RAC3 Location 17q25.3 with 5’ end towards the centromere. Nucleotide 203731-2061912 of contig NT_010663 Located telomeric to the BROV region. Centromeric to LRRC45 - Rac3 - DCXR Local_order telomeric DNA/RNA Note 6 exons, spread out over approximately 2.4 kb Description The Rac3 gene encompasses 6 exons on . Exon 1 encodes residues 1-12, exon 2 residues 13-36, exon 3 residues 37-75, exon 4 residues 76-96, exon 5 residues 97-149 and exon 6 residues 150-192. Transcription Human Rac3 mRNA is a single species of around 1 kb. No splice variants have been reported. Factors that would regulate gene expression on a transcriptional level have not yet been reported. Pseudogene No pseudogenes of Rac3 are reported in human. Protein

Schematic representation of the Rac3 protein (not to scale). Mutations that generate mutants that are locked in a certain conformation - constitutively active or dominant negative - are shown. The C-terminal end contains the CTVM motif that is post- translationally modified the three last amino acid residues are removed and the C residue is geranyl-geranylated. Note The Rac3 gene encodes a single protein of 192 amino acid residues. Description Rac3 is a small 21 kDa GTPase that acts as a molecular switch. In its active form, it is bound to GTP, whereas it is inactive in its GDP-bound form. Racs are controlled by guanidine activating proteins (GEFs) that exchange bound GDP for GTP and by GTPase activating proteins (GAPs) that promote GTP hydrolysis. Because of the hydrophobic isoprenyl moiety at the C-terminal end, it is associated with membranes. In the cytoplasm it associates with the chaperone RhoGDI. Expression Rac3 mRNA was reported in human cell lines including GM04155 (lymphoblastic leukemia), K562 (CML), 5838 (Ewing sarcoma), HL60 (promyelocytic leukemia) and DU4475 (breast cancer). Rac3 expression was reported using semi-quantitative RT/PCR in gastric tumor and adjacent normal tissue as well as gastric cancer cell

Atlas Genet Cytogenet Oncol Haematol 2007; 3 332 lines. Expression of Rac3 using RT/PCR (38 cycles) was reported in human brain, liver, kidney and pancreas poly A RNA and also 19% of brain tumors expressed Rac3 mRNA. Rac3-specific polyclonal antibodies were used to show Rac3 protein in the brain (deep cerebellar nuclei and the pons) in 7 day old mice. Low level expression of mouse rac3 has been reported in bone-marrow-derived monocytes and in B-lineage lymphoblasts using standard and RealTime RT/PCR. Localisation The Rac3 protein is located on endomembranes and cell membranes. Function Rac proteins regulate a variety of functions including cytoskeletal organization, cell cycle, reactive oxygen species production, and vesicle trafficking. In cultured cells they also are involved in cellular transformation. Studies of null mutant Rac3 mice showed that Rac3 regulates cerebellar functions and in a mouse model plays a role in leukemia development caused by the Bcr/Abl oncogene. Point mutations (N26D, F37L, Y40C, N43D) were introduced into different critical residues of the effector domain of Rac3 and the effects of these were investigated on the ability of Rac3 to regulate membrane ruffles, c-jun activation and transformation. Transformation was assayed as the ability to cooperate with activated Raf in focus formation of NIH3T3 cells and the ability to promote growth of these cells in soft agar. Homology Rac3 is most closely related to Rac1 and Rac2. On a nucleotide level human Rac3 has 77% identity with Rac1, 83% identity with Rac2 and 69% identity with RhoG. On an amino acid level, Rac3 and Rac1 differ in 14/192 residues (92% identical), whereas Rac3 and Rac2 differ in 22/192 residues (89% identical). Rac belongs to the extended Rho family of small G-proteins. Biochemically, Rac1 and Rac3 are closely related. Implicated in Entity Breast cancer Note Using in situ hybridization, Rac3 was reported to lies outside of the BROV region commonly deleted in Breast and Ovarian Cancer. Activated Rac3 protein was reported in MDA-435, T47D and MCF7 breast cancer cell lines and 1 of 3 patient samples using a GST-Pak pull-down assay to detect activated Rac. siRNA against Rac3 inhibits SNB19 glioblastoma and BT549 breast cancer cell line invasion in an in vitro assay. It was showed that introduction of a constitutively active Rac3 into the MDA-MB-435 breast cancer cell line caused increased invasion and motility in vitro. Transgenic mice with tissue specific expression of constitutively active (V12)Rac3 in the mammary gland were generated. Post-lactational female mice had delayed involution.

Entity Gastric cancer Note Semi-quantitative RT/PCR was used to examine Rac3 mRNA expression in gastric cancer tissues and 7 gastric cell lines. Rac3 expression was detected in the tumor samples but there was no statistically significant difference between the expression levels in gastric cancer and adjacent non-tumorous tissues. The cell lines had a varying but detectable Rac3 expression.

Entity Brain tumors Note RT-PCR was used to evaluate Rac3 mRNA expression in human brain tumor tissues. Expression of rac3 was reported in 3/9 meningiomas, 1/11 astrocytomas, 1/6 pituitary adenomas. The PCR fragments were subcloned and sequenced, and mutations were reported in Rac3 in 12/19 brain tumors including E10V, V14E, D35N, P35S, N43D, V46A, D57V, R57P, L67V, S83F, V85A, E100G, H104L, P109H, R120H, T125P, S158P, P180T, V182E, V182A, H184L and G186E.

To be noted There is a second gene that is named RAC3 in some publications. This protein is

Atlas Genet Cytogenet Oncol Haematol 2007; 3 333 functionally and structurally unrelated to the small GTPase Rac3. This is the steroid receptor coactivator-3, or nuclear receptor coactivator SRC- 3/AIB1/ACTR/pCIP/RAC3/TRAM-1. Probes 1-12 from NM_005052-links-probes 1: ProbeID:6597734 TaqMan gene expression (TaqMan) probe Hs00414037_g1 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for real time qRT-PCR gene expression profiling. Reagent is available from Applied Biosystems. 2: ProbeID:3104502 Small interfering RNA (siRNA) probe for Homo sapiens gene ras- related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Has been used for RNA interference (RNAi). Reference Chan et al., 2005 3: ProbeID:3104501 Small interfering RNA (siRNA) probe for Homo sapiens gene ras- related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Has been used for RNA interference (RNAi). Reference Chan et al., 2005 4: ProbeID:1163472 Resequencing amplicon (RSA) probe RSA001057586 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery. 5: ProbeID:1163461 Resequencing amplicon (RSA) probe RSA001057592 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery. 6: ProbeID:1157480 Resequencing amplicon (RSA) probe RSA001229136 for Homo sapiens genes ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3) and leucine rich repeat containing 45 (LRRC45). Developed for SNP discovery. 7. ProbeID:1152860 Resequencing amplicon (RSA) probe RSA001400685 for Homo sapiens genes ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3) and leucine rich repeat containing 45 (LRRC45). Developed for SNP discovery. 8: ProbeID:1152824 Resequencing amplicon (RSA) probe RSA001401207 for Homo sapiens genes ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3) and leucine rich repeat containing 45 (LRRC45). Developed for SNP discovery. 9: ProbeID:1151274 Resequencing amplicon (RSA) probe RSA001457703 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery. 10: ProbeID:1151272 Resequencing amplicon (RSA) probe RSA001457859 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery. 11: ProbeID:1151270 Resequencing amplicon (RSA) probe RSA001458006 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery. 12: ProbeID:1151269 Resequencing amplicon (RSA) probe RSA001458005 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery. 13. Chan et al (2005) reported TaqMan primers useful in quantifying human Rac3 expression. 14. Pan et al (2004) reported primers for semi-quantitative RT/PCR for human Rac3 that yielded a 249 bp 15. Hwang et al (2005) reported primers for RT-PCR of human RNA. Fw primer was 5’-AATTCATGCAGGCCATCAAGT-3¹ and the reverse primer 5’- CTAGAAGACGGTGCACTT-3¹. External links Nomenclature Hugo RAC3 GDB RAC3 RAC3 5881 ras-related C3 botulinum toxin substrate 3 (rho family, small GTP Entrez_Gene binding protein Rac3)

Atlas Genet Cytogenet Oncol Haematol 2007; 3 334 Cards Atlas RAC3ID42022ch17q25 GeneCards RAC3 Ensembl RAC3 Genatlas RAC3 GeneLynx RAC3 eGenome RAC3 euGene 5881 Genomic and cartography GoldenPath RAC3 - chr17:77582821-77585368 + 17q25.3 (hg18-Mar_2006) Ensembl RAC3 - 17q25.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene RAC3 Gene and transcription Genbank AF008591 [ ENTREZ ] Genbank AF498966 [ ENTREZ ] Genbank BC009605 [ ENTREZ ] Genbank BC015197 [ ENTREZ ] Genbank BT019443 [ ENTREZ ] RefSeq NM_005052 [ SRS ] NM_005052 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010663 [ SRS ] NT_010663 [ ENTREZ ] AceView RAC3 AceView - NCBI Unigene Hs.45002 [ SRS ] Hs.45002 [ NCBI ] HS45002 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P60763 [ SRS] P60763 [ EXPASY ] P60763 [ INTERPRO ] Interpro IPR003578 GTPase_Rho [ SRS ] IPR003578 GTPase_Rho [ EBI ] Interpro IPR013753 Ras [ SRS ] IPR013753 Ras [ EBI ] Interpro IPR001806 Ras_trnsfrmng [ SRS ] IPR001806 Ras_trnsfrmng [ EBI ] Interpro IPR005225 Small_GTP_bd [ SRS ] IPR005225 Small_GTP_bd [ EBI ] CluSTr P60763 Pfam PF00071 Ras [ SRS ] PF00071 Ras [ Sanger ] pfam00071 [ NCBI-CDD ] Smart SM00174 RHO [EMBL] Blocks P60763 PDB 2C2H [ SRS ] 2C2H [ PdbSum ], 2C2H [ IMB ] 2C2H [ RSDB ] HPRD P60763 Protein Interaction databases DIP P60763 IntAct P60763 Polymorphism : SNP, mutations, diseases OMIM 602050 [ map ] GENECLINICS 602050

Atlas Genet Cytogenet Oncol Haematol 2007; 3 335 SNP RAC3 [dbSNP-NCBI] SNP NM_005052 [SNP-NCI] SNP RAC3 [GeneSNPs - Utah] RAC3] [HGBASE - SRS] HAPMAP RAC3 [HAPMAP] COSMIC RAC3 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family RAC3 [UCSC Family Browser] Browser SOURCE NM_005052 SMD Hs.45002 SAGE Hs.45002 GO nucleotide binding [Amigo] nucleotide binding GO GTPase activity [Amigo] GTPase activity GO protein binding [Amigo] protein binding GO GTP binding [Amigo] GTP binding GO intracellular [Amigo] intracellular small GTPase mediated signal transduction [Amigo] small GTPase mediated signal GO transduction GO endomembrane system [Amigo] endomembrane system GO cell projection biogenesis [Amigo] cell projection biogenesis actin cytoskeleton organization and biogenesis [Amigo] actin cytoskeleton GO organization and biogenesis GO regulation of balance [Amigo] regulation of balance GO neuromuscular process [Amigo] neuromuscular process PubGene RAC3 Other databases Other 03629 database Other RAC3 database Probes Probe RAC3 Related clones (RZPD - Berlin) PubMed PubMed 19 Pubmed reference(s) in LocusLink Bibliography Structure and chromosomal assignment to 22q12 and 17qter of the ras-related Rac2 and Rac3 human genes. Courjal F, Chuchana P, Theillet C, Fort P. Genomics. 1997; 44: 242-246. Medline 9299243

Characterization of RAC3, a novel member of the Rho family. Haataja L, Groffen J, Heisterkamp N. J Biol Chem. 1997; 272: 20384-20388. Medline 9252344

Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated

Atlas Genet Cytogenet Oncol Haematol 2007; 3 336 kinase-dependent pathway. Mira,J.P., Benard,V., Groffen,J., Sanders,L.C. and Knaus, U.G.Proc. Proc. Natl. Acad. Sci. U.S.A. 2000; 97; 185-189. Medline 10618392

The small GTPase RAC3 gene is located within chromosome band 17q25.3 outside and telomeric of a region commonly deleted in breast and ovarian tumours. Morris CM, Haataja L, McDonald M, Gough S, Markie D, Groffen J, Heisterkamp N. Cytogenet Cell Genet. 2000; 89: 18-23. Medline 10894930

Differential distribution of Rac1 and Rac3 in the developing mouse brain: implications for a role of Rac3 in Purkinje cell differentiation. Bolis A, Corbetta S, Cioce A, de Curtis I. Eur J Neurosci. 2003; 18: 2417-2424.

Comparative functional analysis of the Rac GTPases. Haeusler LC, Blumenstein L, Stege P, Dvorsky R, Ahmadian MR. FEBS Lett. 2003; 555: 556-560. Medline 14675773

Targeted expression of activated Rac3 in mammary epithelium leads to defective postlactational involution and benign mammary gland lesions. Leung K, Nagy A, Gonzalez-Gomez I, Groffen J, Heisterkamp N, Kaartinen V. Cells Tissues Organs. 2003; 175: 72-83. Medline 14605486

Expression of seven main Rho family members in gastric carcinoma. Pan Y, Bi F, Liu N, Xue Y, Yao X, Zheng Y, Fan D. Biochem Biophys Res Commun. 2004; 315: 686-691. Medline 14975755

Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells. Baugher PJ, Krishnamoorthy L, Price JE, Dharmawardhane SF. Breast Cancer Res. 2005;7: R965-R974. Medline 16280046

Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Chan AY, Coniglio SJ, Chuang YY, Michaelson D, Knaus UG, Philips MR, Symons M. Oncogene. 2005; 24: 7821-7829 Medline 16027728

Generation of rac3 null mutant mice: role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia. Cho YJ, Zhang B, Kaartinen V, Haataja L, de Curtis I, Groffen J, Heisterkamp N. Mol Cell Biol. 2005; 25: 5777-5785. Medline 15964830

Generation and characterization of Rac3 knockout mice. Corbetta S, Gualdoni S, Albertinazzi C, Paris S, Croci L, Consalez GG, de Curtis I. Mol Cell Biol. 2005; 25: 5763-5776. Medline 15964829

Expression of Rac3 in human brain tumors.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 337 Hwang SL, Chang JH, Cheng TS, Sy WD, Lieu AS, Lin CL, Lee KS, Howng SL, Hong YR. J Clin Neurosci 2005;12: 571-574. Medline 15993075

Rac3-mediated transformation requires multiple effector pathways. Keller PJ, Gable CM, Wing MR, Cox AD. Cancer Res. 2005; 65: 9883-9890. Medline 16267012

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Nora C. Heisterkamp Citation This paper should be referenced as such : Heisterkamp NC . RAC3 (ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3)). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RAC3ID42022ch17q25.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 338 Atlas of Genetics and Cytogenetics in Oncology and Haematology

NUT (nuclear protein in testis) Identity Other names DKFZp434O192 MGC138683 Hugo NUT Location 15q14 (position 32425358-32437221 on the chromosome 15 genomic sequence). Note the gene name NUT has not been approved by the HUGO Committee. DNA/RNA Description The gene consists of 7 exons that span approximately 12 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon and the stop codon are predicted to exon 1 and exon 7, respectively. Transcription The corresponding "wildtype" mRNA transcript is 3.6 kb. Protein Description The open reading frame is predicted to encode an 1127 amino acid protein with an estimated molecular weight of 120 kDa. Expression Northern blot analysis has indicated that the normal expression of the NUT gene is highly restricted to the testis. No investigations have yet been made at the protein level. Localisation Nuclear. Function Unknown. Implicated in Entity Carcinoma with t(15;19)(q14;p13) translocation. Prognosis Carcinoma with t(15;19) translocation is invariably fatal with a rapid clinical course when located to the midline thoracic, head and neck structures. One tumor, displaying the cytogenetic and molecular cytogenetic features of carcinoma with t(15;19) translocation, but located to the iliac bone has been reported successfully cured. It has been suggested that a critical prognostic difference exists between BRD4- NUT/t(15;19) positive tumors and tumors where NUT is rearranged but fused to an as yet unknown partner. Cytogenetics t(15;19)(q14;p13) [reported breakpoints: t(15;19)(q11-15;p13)]. Hybrid/Mutated The t(15;19)(q14;p13) results in an BRD4-NUT chimeric gene where exon 10 of Gene BRD4 is fused to exon 2 of NUT. Abnormal The BRD4-NUT fusion is composed of the N-terminal of BRD4 (amino acids 1-720 out Protein of 1372) and almost the entire protein sequence of NUT (amino acids 6-1127). The N- terminal of BRD4 includes bromodomains 1 and 2 and other, less well characterized functional domains. Oncogenesis It has been suggested that the oncogenic effect of the NUT-BRD4 fusion is caused not only by the abnormal regulation of NUT by BRD4 promoter elements but also by the consequent ectopic expression of NUT in non-germinal tissues. Breakpoints Note The vast majority of reported breakpoints in carcinoma with t(15;19) translocation were assigned to band 19p13, the exception being the cytogenetic interpretation of a 19q13 breakpoint reported once. The reported breakpoints on chromosome 15 have varied

Atlas Genet Cytogenet Oncol Haematol 2007; 3 339 (15q11-q15). External links Nomenclature Hugo - GDB NUT Entrez_Gene NUT 256646 nuclear protein in testis Cards Atlas NUTID41595ch15q14 GeneCards NUT Ensembl NUT Genatlas NUT GeneLynx NUT eGenome NUT euGene 256646 Genomic and cartography GoldenPath NUT - chr15:32425358-32437221 + 15q14 (hg18-Mar_2006) Ensembl NUT - 15q14 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene NUT Gene and transcription Genbank AF482429 [ ENTREZ ] Genbank AK098568 [ ENTREZ ] Genbank AL137416 [ ENTREZ ] Genbank BC033392 [ ENTREZ ] Genbank BC114518 [ ENTREZ ] RefSeq NM_175741 [ SRS ] NM_175741 [ ENTREZ ] RefSeq AC_000058 [ SRS ] AC_000058 [ ENTREZ ] RefSeq NC_000015 [ SRS ] NC_000015 [ ENTREZ ] RefSeq NT_010194 [ SRS ] NT_010194 [ ENTREZ ] RefSeq NW_925840 [ SRS ] NW_925840 [ ENTREZ ] AceView NUT AceView - NCBI Unigene Hs.525769 [ SRS ] Hs.525769 [ NCBI ] HS525769 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q86Y26 [ SRS] Q86Y26 [ EXPASY ] Q86Y26 [ INTERPRO ] CluSTr Q86Y26 Blocks Q86Y26 HPRD Q86Y26 Protein Interaction databases DIP Q86Y26 IntAct Q86Y26 Polymorphism : SNP, mutations, diseases OMIM 608963 [ map ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 340 GENECLINICS 608963 SNP NUT [dbSNP-NCBI] SNP NM_175741 [SNP-NCI] SNP NUT [GeneSNPs - Utah] NUT] [HGBASE - SRS] HAPMAP NUT [HAPMAP] General knowledge Family NUT [UCSC Family Browser] Browser SOURCE NM_175741 SMD Hs.525769 SAGE Hs.525769 GO nucleus [Amigo] nucleus PubGene NUT Other databases Probes Probe NUT Related clones (RZPD - Berlin) PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19). Kees UR, Mulcahy MT, Willoughby MLN. Am J Pediatr Hematol Oncol. 1991; 13: 459-464. Medline 1785673

BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. Cancer Res. 2003; 63: 304-307. Medline 12543779

Midline carcinoma of children and young adults with NUT rearrangement. French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, Nose V, Vargas SO, Moschovi M, Tzortzatou-Stathopoulo F, Miyoshi I, Perez-Atayde AR, Aster JC, Fletcher JA. J Clin Oncol. 2004; 22: 4135-4139. Medline 15483023

Carcinoma with t(15;19) translocation. Marx A, French CA, Fletcher JA. In: World Health Organization classification of tumours. Pathology and genetics of tumours of the lung, thymus, pleura and heart. Travis WD, Brambilla E, M?ller-Hermelink K, Harris CC, editors. Oxford University Press 2004. pp. 185-186.

Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy. Engleson J, Soller M, Panagopoulos I, Dahlen A, Dictor M, Jerkeman M. BMC Cancer. 2006; 6: 69. Medline 16542442

Successful treatment of a child with t(15;19)-positive tumor. Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA. Pediatr Blood Cancer. 2006.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 341 Medline 16435379

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Anna Collin Citation This paper should be referenced as such : Collin A . NUT (nuclear protein in testis). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/NUTID41595ch15q14.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 342 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MUC4 (mucin 4, cell surface associated) Identity Other names sv0-MUC4 Hugo MUC4 Location 3q29 Note MUC4 belongs to the human mucin family, and more specifically to the subgroup of the membrane-anchored mucin. It is an O-glycoprotein that can extend up to 2 micrometer over the cell membrane. It is suggested that MUC4 is translated as a single precursor polypeptide, which is further cleaved at a GDPH site in two subunits, MUC4a and MUC4b. MUC4a is the mucin type subunit and MUC4b is the membrane- bound growth factor like subunit. Both subunits remain non-covalently associated. MUC4 is also found in several secretions such as in the milk. MUC4 along with other mucins is part of the mucus, the viscous gel that covers, moisturizes, and protects all epithelial surfaces. DNA/RNA Note MUC4 gene is located on the chromosome 3 in the region q29, oriented from telomere to centromere and clustered with another mucin gene MUC20. MUC4 is highly polymorphic, harboring numerous sequences repeated in tandem and presenting variable number of tandem repeat (VNTR) polymorphism. The sequence repeated in tandem is localized in exon 2 and is composed of a 48 bp repetitive unit. Due to this highly variable region 27 distinct alleles have been identified for MUC4. Among these, three alleles represent 78.6% of all alleles detected: the 19 kb, 10.5 kb, and 15 kb that present a prevalence of 47%, 18%, and 13.6 % respectively. In addition, 24 alternatively splice transcripts have been identified for MUC4 gene, coding for membrane-anchored and secreted forms.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 343

A: Schematic representation of MUC4 gene and mRNA. The representation is not drawn to scale. B: Example of VTNR polymorphism associated with MUC4 gene. The gDNA of 18 healthy individuals was extracted from the PBMCs and digested by ECORI and PstI endonucleases. Southern blot was hybridized with [32] P-radiolabeled probes of each sequence repeated in tandem.

Description MUC4 gene spans on a 70 kb-long DNA fragment located in 3q29 at the position 196959310-197023545. This position varies from individual to individual due to VNTR polymorphism of several sequences repeated in tandem. The largest domain repeated in tandem is localized in exon 2 and is composed of a motif of 48 bp, repeated up to 400 times. This domain varies from 7 to 19 kb. Three other sequences repeated in tandem with a motif of 15 bp, 26 to 32 bp and 32 bp are positioned in introns 3, 4, and 5 respectively. Theses sequences present also VNTR polymorphism. Various SNPs are reported for MUC4 coding sequence; however, either VNTR or SNP polymorphism have been associated with specific physiological condition or disease. Transcription MUC4 is transcribed in at least 24 distinct splice variant forms in normal and malignant human tissues. Twenty-two of these variants are generated by alternative splicing of the exons at the 3'-extremity and are referred sv1- to sv21-MUC4. Two splice forms are generated by alternative splicing of exon 2 and are called MUC4/X and MUC4/Y. So far, it is unknown if these splice forms are translated, however their deduced amino

Atlas Genet Cytogenet Oncol Haematol 2007; 3 344 acid composition leads to secreted and membrane-anchored proteins. The main isoform of MUC4 (up to 27.5 kb in size), referred to as sv0-MUC4, encodes for full- length MUC4 protein. MUC4 5'-flanking region (over 3.7 kb upstream of the first ATG) has been characterized. Two transcriptionally active units drive MUC4 expression. The proximal promoter is TATA-less, possesses a transcription initiation site at -199, and is mainly composed of GC-rich domains that are potential binding sites for Sp1 and the CACCC box binding protein. Furthermore, a very high density of binding sites for factors known to initiate transcription in TATA-less promoters (Sp1, CACCC box, GRE, AP-1, PEA3 and Med-1) was found within that promoter. The distal promoter is flanked by a TATA box located at -2672/-2668 and three transcriptional initiation sites at -2603, -2604 and -2605. Responsive regions and cis-elements for transcription factors involved in Protein Kinase A, Protein Kinase C, cAMP signaling pathways, in inflammation (NF- kB) and in intestinal (HNF-1, HNF-3, HNF4A, GATA4, GATA-6, CDX1, CDX2) and respiratory ( TITF1, GATA-6, HNF-3b) epithelial cell differentiation have also been identified. Altogether, these results suggest that MUC4 transcription is complex, tightly regulated and involves many signaling pathways. Protein

A: Schematic representation of the modular structure of MUC4. B: Schematic representation of MUC4 protein. The representation is not drawn to scale.

Note MUC4 is a high molecular weight O-glycoprotein. Molecular weight for precursor full- length MUC4 protein may range between 550-930 kDa depending upon the VNTR polymorphism. Classically, the protein moiety represents 20% of the mucin mature molecular weight, leading to a fully glycosylated protein of 4,650 kDa. Description MUC4 is synthesized as a precursor cleaved in two subunits that remain non- covalently link to each other: the mucin type subunit MUC4a of 850 kDa and the membrane-bound growth factor like subunit MUC4b of 80 kDa. MUC4 is a modular protein, composed of very distinct domains.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 345 MUC4a is rich in serine, threonine, and proline residues and present a central domain composed of 16 amino acids repeated in tandem up to 400 times. This repetitive domain is the hallmark of the mucin family. The carboxy-extremity of MUC4a harbors a NIDO and an AMOP domain. The NIDO domain is a domain identified in the nidogen protein and present in several proteins such as the tumor endothelial marker TEM7. TEM7 plays a role in angiogenesis via its NIDO domain. The AMOP domain (adhesion-associated domain in MUC4 and other proteins) is suggested to have a role in cell adhesion. In addition to the AMOP and NIDO domains, analysis of the MUC4a sequence reveals a high degree of similarity with a von Willebrand factor (vWF) D domain. However, none of the cysteine residues that characterized a vWF D domain are conserved in the MUC4 sequence. The MUC4b subunit contains two domains rich in N-glycosylation sites, 3 EGF-like domains, a transmembrane sequence, and a small 22 amino acids long cytoplasmic tail. Expression MUC4 expression is developmentally regulated. In normal physiologic conditions, MUC4 is expressed in the epithelium of the respiratory, digestive and urogenital tracts, with level that varies from tissue to tissues. In the respiratory tract, MUC4 is strongly expressed in the trachea and the lung. In the digestive tract, its main pattern of expression is the oesophagus and the colon. However, MUC4 is not expressed by the annex of the digestive tract such as the liver, the pancreas, and the gallbladder. MUC4 is also expressed by the epithelial cells of the ocular and auditory systems. MUC4 is overexpressed or aberrantly expressed in several diseases, such as inflammatory bowel diseases (Crohn or ulcerative colitis) and malignancy. For instance, MUC4 is overexpressed in lung, oesophagus, and colon cancer and is aberrantly expressed in pancreatic cancer. Neoexpression of MUC4 is observed early in precancerous pancreatic intraepithelial neoplastic lesions that further correlates with the disease progression stages. Many studies has been conducted on human pancreatic or other cancer cell lines in order to elucidate molecular mechanisms responsible for aberrant expression of MUC4 in diseased condition. Initial studies about MUC4 transcriptional regulation showed that Sp1 and Sp3 were important regulators of MUC4 basal expression. EGF and TGF-b growth factors and PKC signaling pathway stimulation results in up regulation of the promoter activity. Whereas TNF-a and IFN-g inflammatory cytokines alone had no effect on MUC4 transcriptional activity, a strong synergistic effect between IFN-g and TNF-a or IFN-g and TGF-b was observed. Activation by IFN-g was then showed to be mediated by STAT-1. More recently, Th1 (IL-2) and Th2 (IL-12, IL- 10) cytokines were shown to interfere with pancreatic tumorigenic environment and possibly modulate MUC4 expression. Subsequent studies aimed at deciphering MUC4 regulation by TGF-b pathway showed that it could be either Smad4-dependent, Smad4-independent (MAPK, PKA, PKC). Retinoic acid induced MUC4 expression was mediated by TGF-b2 and involved RAR-a. TGF-b2 expression in vivo also correlated with that of MUC4 in pancreatic tumors. Interestingly, recent data have shown that MUC4 is negatively regulated by cystic fibrosis transmembrane regulator (CFTR), a chloride channel that is defective in CF. In oesophageal cancer cells, MUC4 is regulated by bile acids via activation of phosphatidylinositol 3-kinase pathway or activation of HNF-1a. Studies in lung adenocarcinoma cell lines focused on cytokines involved in airway inflammation showed that MUC4 is regulated by IL-4 via JAK-3 and IL-9. Identification of the molecular mechanisms governing MUC4 expression will be very informative to assign direct roles to that mucin in carcinogenesis and on the biological properties of the tumor cell and should provide new tools in the future for therapeutic intervention. Localisation In normal physiologic situation, MUC4 is localized in the membrane at the apical region of the cells and in the mucus secretion. During cancer development, MUC4 exhibits diffuse expression in both the membrane and cytoplasm. Furthermore, due to loss of cell polarity, defined apical localization of MUC4 is disrupted. Function MUC4 transmembrane mucin is a highly glycosylated protein with an extended rigid extracellular domain that may confer a role for MUC4 as a molecular sensor between the extracellular milieu and the epithelial cell. MUC4 is also the putative ligand of

Atlas Genet Cytogenet Oncol Haematol 2007; 3 346 ERBB2 oncogenic receptor and thus may participate in cell signalling, influence cell proliferation, tumor progression, tumor cell morphology, cell polarity and escape to immune surveillance. Moreover, its over-expression in numerous cancers (lung, oesophagus, intestine, pancreas, etc.) is often associated with a poor prognosis. Functional role of MUC4 in pancreatic tumor growth and metastasis has also been recently demonstrated. MUC4 consists of two subunits, the extracellular highly glycosylated mucin subunit (MUC4-a) and a transmembrane subunit containing three EGF-like domains (MUC4- b). These subunits of MUC4 may confer diverse functions to MUC4. The large sized extracellular subunit may provide the anti-adhesive or adhesive functions. The anti- adhesive function of MUC4 may aid in loosening the tumor cell-ECM interactions and facilitating the dissemination of tumor cells. Whereas, the high degree of glycosylation present in tandem repeat domain of MUC4 mucin can help in the adhesion of tumor cells to secondary sites and hence promote metastasis. Another important function provided by MUC4 mucin is modulation of HER-2/ERBB2 mediated signaling. MUC4, an interaction partner of the proto-oncogene HER2, induces its localization at the cell membrane and triggers the signaling pathways downstream to HER-2 activation. The consequences of such interactions and signaling activation lead to malignant transformation. Hence, dysregulation of MUC4 expression, a protective cell surface protein, may have deleterious effects. The association of MUC4 with ERBB2 involves its translocation from the basolateral toward the apical membrane and increasing the membrane stability. Regulation of MUC4 and ERBB2 by PEA3 transcription factor was found to be conversely correlated, stressing the fact that balance between MUC4 and ErbB2 will orientate the tumor cell toward either differentiation or proliferation. Under normal physiological conditions, MUC4 provides protection, lubrication and moisturization to the epithelial surfaces by trapping the foreign particles and preventing their accessibility to the cells. Being expressed in fetus tissue before differentiation, MUC4 is also suggested to play role in morphogenic functions. Homology Several orthologues of MUC4 are totally or partially characterized. Mouse (mMuc4) and rat (rMuc4 or SMC for sialomucin complex) are fully identified and present 60 to 70% homology with human MUC4. Mouse mMuc4 is localized on the chromosome 16. Partial cDNA sequences of porcine, chinchilla, monkey, and dog Muc4 were also recently identified. Implicated in Entity Pancreatic adenocarcinoma. Disease Worldwide, pancreatic cancer is the eleventh most common cancer and the fourth leading cause of cancer related death among men and women. Pancreatic cancer presents a 5-years survival rate of 5%. The incidence and age-adjusted mortality rate are almost equal, underscoring the aggressive nature of the disease. Prognosis The DU-PAN-2 antibody that recognizes a tumor-associated antigen carries by the MUC4 protein is in clinical used in Japan for diagnostic of pancreatic adenocarcinoma. MUC4 is aberrantly expressed by 80% of the adenocarnicoma of the pancreatic gland while not expressed in the normal pancreas or in pancreatitis. In addition, MUC4 is expressed early in the onset of pancreatic cancer, already detected in the pancreatic intraepithelial neoplasia (PanIN) of stage I. Oncogenesis In in vivo model, MUC4 was shown to promote tumor progression and metastasis. On clinical sample, patients negative for MUC4 expression has a better prognosis and a longer life time. External links Nomenclature Hugo MUC4 GDB MUC4 Entrez_Gene MUC4 4585 mucin 4, cell surface associated Cards

Atlas Genet Cytogenet Oncol Haematol 2007; 3 347 Atlas MUC4ID41459ch3q29 GeneCards MUC4 Ensembl MUC4 Genatlas MUC4 GeneLynx MUC4 eGenome MUC4 euGene 4585 Genomic and cartography GoldenPath MUC4 - 3q29 chr3:196959311-197023545 - 3q29 (hg18-Mar_2006) Ensembl MUC4 - 3q29 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene MUC4 Gene and transcription Genbank AF058803 [ ENTREZ ] Genbank AF058804 [ ENTREZ ] Genbank AF177925 [ ENTREZ ] Genbank AJ000281 [ ENTREZ ] Genbank AJ010901 [ ENTREZ ] RefSeq NM_004532 [ SRS ] NM_004532 [ ENTREZ ] RefSeq NM_018406 [ SRS ] NM_018406 [ ENTREZ ] RefSeq NM_138297 [ SRS ] NM_138297 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_029928 [ SRS ] NT_029928 [ ENTREZ ] RefSeq NW_921840 [ SRS ] NW_921840 [ ENTREZ ] AceView MUC4 AceView - NCBI Unigene Hs.677523 [ SRS ] Hs.677523 [ NCBI ] HS677523 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O75456 [ SRS] O75456 [ EXPASY ] O75456 [ INTERPRO ] CluSTr O75456 Blocks O75456 HPRD O75456 Protein Interaction databases DIP O75456 IntAct O75456 Polymorphism : SNP, mutations, diseases OMIM 158372 [ map ] GENECLINICS 158372 SNP MUC4 [dbSNP-NCBI] SNP NM_004532 [SNP-NCI] SNP NM_018406 [SNP-NCI] SNP NM_138297 [SNP-NCI]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 348 SNP MUC4 [GeneSNPs - Utah] MUC4] [HGBASE - SRS] HAPMAP MUC4 [HAPMAP] General knowledge Family MUC4 [UCSC Family Browser] Browser SOURCE NM_004532 SOURCE NM_018406 SOURCE NM_138297 SMD Hs.677523 SAGE Hs.677523 GO ErbB-2 class receptor binding [Amigo] ErbB-2 class receptor binding GO protein binding [Amigo] protein binding GO integral to plasma membrane [Amigo] integral to plasma membrane GO cell adhesion [Amigo] cell adhesion GO cell-matrix adhesion [Amigo] cell-matrix adhesion GO membrane [Amigo] membrane PubGene MUC4 Other databases Probes Probe MUC4 Related clones (RZPD - Berlin) PubMed PubMed 46 Pubmed reference(s) in LocusLink Bibliography Mucin 4 (MUC4) gene: regional assignment (3q29) and RFLP analysis. Gross MS, Guyonnet-Duperat V, Porchet N, Bernheim A, Aubert JP, Nguyen VC. Ann Genet. 1992; 35: 21-26. Medline 1351710

Mucin gene expression in human embryonic and fetal intestine. Buisine MP, Devisme L, Savidge TC, Gespach C, Gosselin B, Porchet N, Aubert JP. Gut. 1998; 43(4): 519-524. Medline 9824580

Human mucin gene MUC4: organization of its 5'-region and polymorphism of its central tandem repeat array. Nollet S, Moniaux N, Maury J, Petitprez D, Degand P, Laine A, Porchet N, Aubert JP. Biochem J. 1998; 332: 739-748. Medline 9620877

Developmental mucin gene expression in the human respiratory tract. Buisine MP, Devisme L, Copin MC, Durand-Reville M, Gosselin B, Aubert JP, Porchet N. Am J Respir Cell Mol Biol. 1999; 20(2): 209-218. Medline 9922211

MUC4 and MUC5B transcripts are the prevalent mucin messenger ribonucleic acids of the human endocervix. Gipson IK, Spurr-Michaud S, Moccia R, Zhan Q, Toribara N, Ho SB, Gargiulo AR, Hill JA. Biol Reprod. 1999; 60: 58-64.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 349 Medline 9858486

Complete sequence of the human mucin MUC4: a putative cell membrane-associated mucin. Moniaux N, Nollet S, Porchet N, Degand P, Laine A, Aubert JP. Biochem J. 1999; 338: 325-333. Medline 10024507

Developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. II. Duodenum and liver, gallbladder, and pancreas. Buisine MP, Devisme L, Degand P, Dieu MC, Gosselin B, Copin MC, Aubert JP, Porchet N. J Histochem Cytochem. 2000; 48(12): 1667-1676. Medline 11101635

Developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. I. Stomach. A relationship to gastric carcinoma. Buisine MP, Devisme L, Maunoury V, Deschodt E, Gosselin B, Copin MC, Aubert JP, Porchet N. J Histochem Cytochem. 2000; 48(12): 1657-1666. Medline 11101634

Retinoic Acid Dependent Transforming Growth Factor-beta2-Mediated Induction of MUC4 Mucin Expression in Human Pancreatic Tumor Cells Follows Retinoic Acid Receptor-alpha Signaling Pathway. Choudhury A, Singh RK, Moniaux N, El-Metwally TH, Aubert JP, Batra SK. J Biol Chem. 2000; 275: 33929-33936. Medline 10938282

Alternative splicing generates a family of putative secreted and membrane-associated MUC4 mucins. Moniaux N, Escande F, Batra SK, Porchet N, Laine A, Aubert JP. Eur J Biochem. 2000; 267: 4536-4544. Medline 10880978

Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significance. Andrianifahanana M, Moniaux N, Schmied BM, Ringel J, Friess H, Hollingsworth MA, Buchler MW, Aubert JP, Batra SK. Clin Cancer Res. 2001; 7: 4033-4040. Medline 11751498

Alternate splicing at the 3'-end of the human pancreatic tumor-associated mucin MUC4 cDNA. Choudhury A, Moniaux N, Ringel J, King J, Moore E, Aubert JP, Batra SK. Teratogenesis,Carcinogenesis, and Mutagenesis. 2001; 21: 83-96. Medline 11135323

Characterization of human mucin gene MUC4 promoter: importance of growth factors and proinflammatory cytokines for its regulation in pancreatic cancer cells. Perrais M, Pigny P, Ducourouble MP, Petitprez D, Porchet N, Aubert JP, Van SI. J Biol Chem. 2001; 276: 30923-30933. Medline 11418607

Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. Carraway KL, Perez A, Idris N, Jepson S, Arango M, Komatsu M, Haq B, Price-Schiavi SA, Zhang J, Carraway CA. Prog Nucleic Acid Res Mol Biol. 2002; 71: 149-185.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 350 Medline 12102554

Genomic organization of MUC4 mucin gene. Towards the characterization of splice variants. Escande F, Lemaitre L, Moniaux N, Batra SK, Aubert JP, Buisine MP. Eur J Biochem. 2002; 269: 3637-3644. Medline 12153560

MUC4 Expression increases progressively in pancreatic intraepithelial neoplasia (PanIN). Swart MJ, Batra SK, Varshney GC, Hollingsworth MA, Yeo CJ, Cameron JL, Willentz RE, Hruban RH, Argani P. Am J Clin Pathol. 2002; 117: 791-796. Medline 12090430

Aberrant Expression of MUC3 and MUC4 Membrane-Associated Mucins and Sialyl Lex Antigen in Pancreatic Intraepithelial Neoplasia. Park HU, Kim JW, Kim GE, Bae HI, Crawley SC, Yang SC, Gum J, Jr., Batra SK, Rousseau K, Swallow DM, Sleisenger MH, Kim YS. Pancreas. 2003; 26: 48-54. Medline 12657964

Muc4/sialomucin complex, the intramembrane ErbB2 ligand, translocates ErbB2 to the apical surface in polarized epithelial cells. Ramsauer VP, Carraway CA, Salas PJ, Carraway KL. J Biol Chem. 2003; 278(32): 30142-30147. Epub 2003 May 14. Medline 12748185

MUC4 is increased in high grade intraepithelial neoplasia in Barrett's oesophagus and is associated with a proapoptotic Bax to Bcl-2 ratio. Bax DA, Haringsma J, Einerhand AW, van DH, Blok P, Siersema PD, Kuipers EJ, Kusters JG. J Clin Pathol. 2004; 57: 1267-1272. Medline 15563666

MUC4 mucin expression in human pancreatic tumours is affected by organ environment: the possible role of TGFbeta2. Choudhury A, Moniaux N, Ulrich AB, Schmied BM, Standop J, Pour PM, Gendler SJ, Hollingsworth MA, Aubert JP, Batra SK. Br J Cancer. 2004; 90: 657-664. Medline 14760381

Mucins in cancer: protection and control of the cell surface. Hollingsworth MA, Swanson BJ. Nat Rev Cancer. 2004; 4(1): 45-60. Medline 14681689

A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-beta in pancreatic carcinogenesis. Jonckheere N, Perrais M, Mariette C, Batra SK, Aubert JP, Pigny P, Van Seuningen I. Oncogene. 2004; 23(34): 5729-5738. Medline 15184872

Transcriptional regulation of human mucin MUC4 by bile acids in oesophageal cancer cells is promoter-dependent and involves activation of the phosphatidylinositol 3-kinase signalling pathway. Mariette C, Perrais M, Leteurtre E, Jonckheere N, Hemon B, Pigny P, Batra S, Aubert JP, Triboulet JP, Van Seuningen I.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 351 Biochem J. 2004; 377: 701-708. Medline 14583090

Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy. Moniaux N, Andrianifahanana M, Brand RE, Batra SK. Br J Cancer. 2004; 91(9): 1633-1638. Medline 15494719

Generation and Characterization of Anti-MUC4 Monoclonal Antibodies Reactive with Normal and Cancer Cells in Humans. Moniaux N, Varshney GC, chauhan SC, Copin MC, jain M, Wittel UA, Andrianifahanana M, Aubert JP, Batra SK. J Histochem Cytochem. 2004; 52: 253-261. Medline 14729877

Inhibition of MUC4 Expression Suppresses Pancreatic Tumor Cell Growth and Metastasis. Singh AP, Moniaux N, chauhan SC, Meza JL, Batra SK. Cancer Res. 2004; 64: 622-630. Medline 14744777

Synergistic induction of the MUC4 mucin gene by interferon-gamma and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways. Andrianifahanana M, Agrawal A, Singh AP, Moniaux N, Van S, I, Aubert JP, Meza J, Batra SK. Oncogene. 2005; 24: 6143-6154. Medline 16007204

MUC4-expressing pancreatic adenocarcinomas show elevated levels of both T1 and T2 cytokines: potential pathobiologic implications. Andrianifahanana M, Chauhan SC, Choudhury A, Moniaux N, Brand RE, Sasson AA, Pour PM, Batra SK. Am J Gastroenterol. 2006; 101(10): 2319-2329. Medline 17032197

Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125). Chauhan SC, Singh AP, Ruiz F, Johansson SL, Jain M, Smith LM, Moniaux N, Batra SK. Mod Pathol. 2006; 19(10): 1386-1394. Medline 16880776

IL-9 modulated MUC4 gene and glycoprotein expression in airway epithelial cells. Damera G, Xia B, Ancha HR, Sachdev GP. Biosci Rep. 2006; 26(1): 55-67. Medline 16779668

IL-4 induced MUC4 enhancement in respiratory epithelial cells in vitro is mediated through JAK-3 selective signaling. Damera G, Xia B, Sachdev GP. Respir Res. 2006; 7: 39. Medline 16551361

The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3. Funes M, Miller JK, Lai C, Carraway KL 3rd, Sweeney C. J Biol Chem. 2006; 281(28): 19310-19319. Epub 2006 May 11.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 352 Medline 16690615

Membrane mucin Muc4 induces density-dependent changes in ERK activation in mammary epithelial and tumor cells: role in reversal of contact inhibition. Pino V, Ramsauer VP, Salas P, Carothers Carraway CA, Carraway KL. J Biol Chem. 2006; 281(39): 29411-29420. Epub 2006 Aug 4. Medline 16891313

Muc4-ErbB2 complex formation and signaling in polarized CACO-2 epithelial cells indicate that Muc4 acts as an unorthodox ligand for ErbB2. Ramsauer VP, Pino V, Farooq A, Carothers Carraway CA, Salas PJ, Carraway KL. Mol Biol Cell. 2006; 17(7): 2931-2941. Epub 2006 Apr 19. Medline 16624867

Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas. Singh AP, Chauhan SC, Bafna S, Johansson SL, Smith LM, Moniaux N, Lin MF, Batra SK. Prostate. 2006; 66(4): 421-429. Medline 16302265

Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy. Singh AP, Chaturvedi P, Batra SK. Cancer Res. 2007; 67(2): 433-436. Medline 17234748

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms. Singh AP, Chauhan SC, Andrianifahanana M, Moniaux N, Meza JL, Copin MC, van Seuningen I, Hollingsworth MA, Aubert JP, Batra SK. Oncogene. 2007; 26(1): 30-41. Medline 16799633

Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1alpha. Piessen G, Jonckheere N, Vincent A, Hemon B, Ducourouble MP, Copin MC, Mariette C, Van Seuningen I. Biochem J. 2007; 402(1): 81-91. Medline 17037983

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written Nicolas Moniaux, Pallavi Chaturvedi, Isabelle Van Seuningen, Nicole 02-2007 Porchet, Ajay P. Singh, Surinder K. Batra Citation This paper should be referenced as such : Moniaux N, Chaturvedi P, Van Seuningen I, Porchet N, Singh AP, Batra SK . MUC4 (mucin 4, cell surface associated). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/MUC4ID41459ch3q29.html

Atlas Genet Cytogenet Oncol Haematol 2007; 3 353

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 354 Atlas of Genetics and Cytogenetics in Oncology and Haematology

JAG2 (Human Jagged2) Identity Other names HJ2 Jagged2 Hugo JAG2 Location Human Jagged2 (jag2), a ligand for Notch receptor, was mapped in the chromosomal region 14q32. DNA/RNA Description Human Jagged2 gene contains approximately 5,077 bps including 26 exons and a putative promoter region. In addition to a TATA box and a CAC binding site, the promoter region also contains several transcription factor binding sites like NF- kappaB, E47, E12, E2F etc. JAG2 gene has a structural similarity (overall 62% at nucleotide level) with JAG1, though JAG1 is located at chromosomal region 20p12. Protein Description The predicted JAG2 protein is approximately 1,238-amino acid long. It has several recognizable motifs, including a signal peptide, 16 EGF-like repeats, a transmembrane domain, and a short cytoplasmic domain. Expression In human, JAG2 is expressed at high levels in the heart, the skeletal muscle and the pancreas. Implicated in Entity Multiple Myeloma Disease The NOTCH ligand, JAG2, has been found to be overexpressed in malignant plasma cells from multiple myeloma (MM) patients and cell lines but not in nonmalignant plasma cells from tonsils, bone marrow from healthy individuals, or patients with other malignancies. Since MM cells have been shown to induce IL-6 expression in stromal cells in a largely cell contact-dependent manner, it has been concluded that MM cells induce production of IL-6 in stromal cells through overexpression of JAG2. Once secreted, IL-6 enhances proliferation of myeloma cells in a paracrine fashion.

Schematic representation of the physiological activation of NOTCH, with Cell 1 (MM plasma cell) expressing JAG2 and Cell 2 (Stromal cell) NOTCH. A: JAG2 binds NOTCH via cell-to-cell contact. B: Binding of JAG2 induces a proteolytic cleavage of the intracellular part of NOTCH

Atlas Genet Cytogenet Oncol Haematol 2007; 3 355 (NOTCH-IC). C: Once cleaved, NOTCH-IC is translocated into the nucleus. D: Once in the nucleus, NOTCH-IC will be able to bind to downstream effectors such as CBF1, to activate, for example, the IL-6 gene transcription.

Oncogenesis The induction of IL-6 secretion has been blocked in vitro by interference with anti- Notch-1 monoclonal antibodies raised against the binding sequence of Notch-1 with JAG2. Taken together, these results indicate that JAG2 over expression may be an early event in the pathogenesis of multiple myeloma involving IL-6 production.

External links Nomenclature Hugo JAG2 GDB JAG2 Entrez_Gene JAG2 3714 jagged 2 Cards Atlas JAG2ID41030ch14q32 GeneCards JAG2 Ensembl JAG2 Genatlas JAG2 GeneLynx JAG2 eGenome JAG2 euGene 3714 Genomic and cartography JAG2 - Human Jagged2 (jag2), a ligand for Notch receptor, was mapped in the GoldenPath chromosomal region 14q32. chr14:104679122-104706206 - 14q32 (hg18- Mar_2006) Ensembl JAG2 - 14q32 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene JAG2 Gene and transcription Genbank AF003521 [ ENTREZ ] Genbank AF020201 [ ENTREZ ] Genbank AF029778 [ ENTREZ ] Genbank AF029779 [ ENTREZ ] Genbank BC032053 [ ENTREZ ] RefSeq NM_002226 [ SRS ] NM_002226 [ ENTREZ ] RefSeq NM_145159 [ SRS ] NM_145159 [ ENTREZ ] RefSeq AC_000057 [ SRS ] AC_000057 [ ENTREZ ] RefSeq NC_000014 [ SRS ] NC_000014 [ ENTREZ ] RefSeq NT_026437 [ SRS ] NT_026437 [ ENTREZ ] RefSeq NW_925561 [ SRS ] NW_925561 [ ENTREZ ] AceView JAG2 AceView - NCBI Unigene Hs.433445 [ SRS ] Hs.433445 [ NCBI ] HS433445 [ spliceNest ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 356 Protein : pattern, domain, 3D structure SwissProt Q9Y219 [ SRS] Q9Y219 [ EXPASY ] Q9Y219 [ INTERPRO ] Prosite PS00010 ASX_HYDROXYL [ SRS ] PS00010 ASX_HYDROXYL [ Expasy ] Prosite PS51051 DSL [ SRS ] PS51051 DSL [ Expasy ] Prosite PS00022 EGF_1 [ SRS ] PS00022 EGF_1 [ Expasy ] Prosite PS01186 EGF_2 [ SRS ] PS01186 EGF_2 [ Expasy ] Prosite PS50026 EGF_3 [ SRS ] PS50026 EGF_3 [ Expasy ] Prosite PS01187 EGF_CA [ SRS ] PS01187 EGF_CA [ Expasy ] Prosite PS01208 VWFC_1 [ SRS ] PS01208 VWFC_1 [ Expasy ] Prosite PS50184 VWFC_2 [ SRS ] PS50184 VWFC_2 [ Expasy ] CluSTr Q9Y219 Blocks Q9Y219 HPRD Q9Y219 Protein Interaction databases DIP Q9Y219 IntAct Q9Y219 Polymorphism : SNP, mutations, diseases OMIM 602570 [ map ] GENECLINICS 602570 SNP JAG2 [dbSNP-NCBI] SNP NM_002226 [SNP-NCI] SNP NM_145159 [SNP-NCI] SNP JAG2 [GeneSNPs - Utah] JAG2] [HGBASE - SRS] HAPMAP JAG2 [HAPMAP] COSMIC JAG2 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family JAG2 [UCSC Family Browser] Browser SOURCE NM_002226 SOURCE NM_145159 SMD Hs.433445 SAGE Hs.433445 GO cell fate determination [Amigo] cell fate determination GO Notch binding [Amigo] Notch binding GO calcium ion binding [Amigo] calcium ion binding GO protein binding [Amigo] protein binding GO integral to plasma membrane [Amigo] integral to plasma membrane GO cell cycle [Amigo] cell cycle GO cell communication [Amigo] cell communication GO Notch signaling pathway [Amigo] Notch signaling pathway GO multicellular organismal development [Amigo] multicellular organismal development GO spermatogenesis [Amigo] spermatogenesis GO growth factor activity [Amigo] growth factor activity GO auditory receptor cell fate commitment [Amigo] auditory receptor cell fate

Atlas Genet Cytogenet Oncol Haematol 2007; 3 357 commitment GO membrane [Amigo] membrane GO cell differentiation [Amigo] cell differentiation GO T cell differentiation [Amigo] T cell differentiation GO regulation of cell migration [Amigo] regulation of cell migration GO regulation of cell proliferation [Amigo] regulation of cell proliferation GO thymic T cell selection [Amigo] thymic T cell selection PubGene JAG2 Other databases Probes Probe JAG2 Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography The Jagged2 gene maps to chromosome 12 and is a candidate for the lgl and sm mutations. Lan Y, Jiang R, Shawber C, Weinmaster G, Gridley T. Mammalian Genome. 1997; 8: 875-876. Medline 9341252

Human ligands of the Notch receptor. Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S. Am. J. Path. 1999; 154: 785-794. Medline 10079256

Characterization, chromosomal localization, and the complete 30-kb DNA sequence of the human Jagged2 (JAG2) gene. Deng Y, Madan A, Banta AB, Friedman C, Trask BJ, Hood L, Li L. Genomics. 2000; 63: 133-138. Medline 10662552

Mouse Jagged2 is differentially expressed in hematopoietic progenitors and endothelial cells and promotes the survival and proliferation of hematopoietic progenitors by direct cell-to-cell contact. Tsai S, Fero J, Bartelmez S. Blood. 2000; 96: 950-957. Medline 10910909

The notch ligands, delta-1 and jagged-2, are substrates for presenilin-dependent gamma- secretase cleavage. Ikeuchi T, Sisodia SS. J. Biol. Chem. 2003; 278: 7751-7754. Medline 12551931

Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Houde C, Li Y, Song L, Barton K, Zhang Q, Godwin J, Nand S, Toor A, Alkan S, Smadja NV, Avet- Loiseau H, Lima CS, Miele L, Coignet LJ. Blood. 2004; 104: (12), 3697-3704. Medline 15292061

Atlas Genet Cytogenet Oncol Haematol 2007; 3 358 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Pushpankur Ghoshal, Lionel J Coignet Citation This paper should be referenced as such : Ghoshal P, Coignet LJ . JAG2 (Human Jagged2). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/JAG2ID41030ch14q32.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 359 Atlas of Genetics and Cytogenetics in Oncology and Haematology

HSPH1 (heat shock 105kDa/110kDa protein 1) Identity Other names HSP105alpha HSP105beta HSP110 HSP105 KIAA0201 NY-CO-25 Hugo HSPH1 Location 13q12.3 DNA/RNA

Genomic organization of the mouse HSP105 gene. The linear map of the exon-intron structure is shown schematically. Exons are represented as numbered boxes. Two alternative splicing patterns gave rise to HSP105alpha and HSP105beta transcripts. ATG and TAG indicate the positions of initiation and termination codons, respectively. (DDBJ/EMBL/GenBank DNA databases with accession Nos. AB005267-AB005282).

Description 18 exons on 22 kb Transcription Hsp105alpha is transcribed constitutively and also by a variety of stresses. 4 kb mRNA Hsp105beta is an alternative spliced isoform only produced during heat shock at 42 degree. Protein

Shematic structures of HSP105alpha and HSP105beta proteins. Shaded box represents the spliced out region of HSP105alpha which is lacking in HSP105beta.

Description Hsp105alpha: 858 amino acids, 105 kDa; contains an ATP binding domain (residues

Atlas Genet Cytogenet Oncol Haematol 2007; 3 360 1-383), b-sheet domain (residues 384-511), loop domain (residues 512-607) and alpha-helix domain (residues 608-858). Expression wide, highly expressed in brain Localisation Hsp105alpha, cytoplasmic; Hsp105beta, nuclear Function Hsp105alpha and Hsp105beta suppress the aggregation of denatured proteins; function as a substitute for Hsp70 family proteins to suppress the aggregation of denatured proteins in cells under severe stress; regulate substrate binding cycle of Hsp70/Hsc70 by inhibiting the ATPase activity of Hsp70/Hsc70. Homology With mouse apg-1, mouse apg-2, sea urchin egg receptor, C. elegans 86.9-kDa protein, A. thaliana hsp91 and S. cerevisiae SSE1, human hsp70 and human hsc70. Implicated in Entity Lung cancers Prognosis Poor Oncogenesis Low expression of hsp105 was identified as predictors of survival in lung adenocarcinomas.

Entity Colorectal cancers Prognosis Survival is not much more than 50% after 5 years. Oncogenesis Overexpression of hsp105 is a late event in the colorectal adenoma-carcinoma sequence.

External links Nomenclature Hugo HSPH1 GDB HSPH1 Entrez_Gene HSPH1 10808 heat shock 105kDa/110kDa protein 1 Cards Atlas HSPH1ID40891ch13q12 GeneCards HSPH1 Ensembl HSPH1 Genatlas HSPH1 GeneLynx HSPH1 eGenome HSPH1 euGene 10808 Genomic and cartography GoldenPath HSPH1 - 13q12.3 chr13:30608765-30634117 - 13q12.3 (hg18-Mar_2006) Ensembl HSPH1 - 13q12.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene HSPH1 Gene and transcription Genbank AB003333 [ ENTREZ ] Genbank AB003334 [ ENTREZ ] Genbank AF039695 [ ENTREZ ] Genbank BC018124 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 361 Genbank BC037553 [ ENTREZ ] RefSeq NM_006644 [ SRS ] NM_006644 [ ENTREZ ] RefSeq AC_000056 [ SRS ] AC_000056 [ ENTREZ ] RefSeq NC_000013 [ SRS ] NC_000013 [ ENTREZ ] RefSeq NT_024524 [ SRS ] NT_024524 [ ENTREZ ] RefSeq NW_925473 [ SRS ] NW_925473 [ ENTREZ ] AceView HSPH1 AceView - NCBI Unigene Hs.36927 [ SRS ] Hs.36927 [ NCBI ] HS36927 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q92598 [ SRS] Q92598 [ EXPASY ] Q92598 [ INTERPRO ] Prosite PS00297 HSP70_1 [ SRS ] PS00297 HSP70_1 [ Expasy ] Prosite PS00329 HSP70_2 [ SRS ] PS00329 HSP70_2 [ Expasy ] Prosite PS01036 HSP70_3 [ SRS ] PS01036 HSP70_3 [ Expasy ] Interpro IPR001023 Hsp70 [ SRS ] IPR001023 Hsp70 [ EBI ] Interpro IPR013126 Hsp_70 [ SRS ] IPR013126 Hsp_70 [ EBI ] CluSTr Q92598 Pfam PF00012 HSP70 [ SRS ] PF00012 HSP70 [ Sanger ] pfam00012 [ NCBI-CDD ] Prodom PD000089 Hsp70[INRA-Toulouse] Q92598 HS105_HUMAN [ Domain structure ] Q92598 HS105_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q92598 HPRD Q92598 Protein Interaction databases DIP Q92598 IntAct Q92598 Polymorphism : SNP, mutations, diseases OMIM 610703 [ map ] GENECLINICS 610703 SNP HSPH1 [dbSNP-NCBI] SNP NM_006644 [SNP-NCI] SNP HSPH1 [GeneSNPs - Utah] HSPH1] [HGBASE - SRS] HAPMAP HSPH1 [HAPMAP] General knowledge Family HSPH1 [UCSC Family Browser] Browser SOURCE NM_006644 SMD Hs.36927 SAGE Hs.36927 GO nucleotide binding [Amigo] nucleotide binding GO ATP binding [Amigo] ATP binding GO cytoplasm [Amigo] cytoplasm GO response to unfolded protein [Amigo] response to unfolded protein PubGene HSPH1 Other databases

Atlas Genet Cytogenet Oncol Haematol 2007; 3 362 Probes Probe HSPH1 Related clones (RZPD - Berlin) PubMed PubMed 21 Pubmed reference(s) in LocusLink Bibliography Cloning and expression of murine high molecular mass heat shock proteins, HSP105. Yasuda K, Nakai A, Hatayama T, Nagata K. J. Biol. Chem. 1995; 270: 29718-29723. Medline 8530361

Molecular cloning, expression and localization of human 105 kDa heat shock protein, hsp105. Ishihara K, Yasuda K, Hatayama T. Biochim. Biophys. Acta 1999; 1444: 138-142. Medline 9931472

Genomic cloning and promoter analysis of mouse 105-kda heat shock protein (HSP105) gene. Yasuda K, Ishihara K, Nakashima K, Hatayama T Medline 10066425

Gene cloning of immunogenic antigens overexpressed in pancreatic cancer. Nakatsura T, Senju S, Yamada K, Jotsuka T, Ogawa M, Nishimura Y. Biochem Biophys Res Commun 2001; 281: 936-944. Medline 11237751

Differential, stage-dependent expression of Hsp70, Hsp110 and Bcl-2 in colorectal cancer. Hwang TS, Han HS, Choi HK, Lee YJ, Kim YJ, Han MY, Park YM. J. Gastroenterol. Hepatol. 2003; 18: 690-700. Medline 12753152

Heat shock protein 105 is overexpressed in a variety of human tumors. Kai M, Nakatsura T, Egami H, Senju S, Nishimura Y, Ogawa M . Oncol Rep 2003; 10: 1777-1782. Medline 14534695

Hsp105 but not Hsp70 family proteins suppress the aggregation of heat-denatured protein in the presence of ADP. Yamagishi N, Ishihara K, Saito Y, Hatayama T. FEBS Lett. 2003; 555: 390-396. Medline 14644449

Hsp105alpha suppresses Hsc70 chaperone activity by inhibiting Hsc70 ATPase activity. Yamagishi, N, Ishihara, K, Hatayama T. J. Biol. Chem. 2004; 279: 41727-41733. Medline 15292236

DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4+ T cells and CD8+ T cells. Miyazaki M, Nakatsura T, Yokomine K, Senju S, Monji M, Hosaka S, Komori H, Yoshitake Y, Motomura Y, Minohara M, Kubo T, Ishihara K, Hatayama T, Ogawa M, Nishimura Y. Cancer Sci. 2005; 96: 695-705. Medline 16232202

Atlas Genet Cytogenet Oncol Haematol 2007; 3 363 Hsp105 family proteins suppress staurosporine-induced apoptosis by inhibiting the translocation of Bax to mitochondria in HeLa cells. Yamagishi, N, Ishihara, K, Saito, Y, Hatayama T. Exp. Cell Res. 2006; 312: 3215-3223 Medline 16857185

Synthetic small interfering RNA targeting heat shock protein 105 induces apoptosis of various cancer cells both in vitro and in vivo. Hosaka S, Nakatsura T, Tsukamoto H, Hatayama T, Baba H, Nishimura Y. Cancer Sci. 2006; 97: 623-632. Medline 16827803

Heat shock protein 105 is overexpressed in squamous cell carcinoma and extramammary Paget disease but not in basal cell carcinoma. Muchemwa FC, Nakatsura T, Ihn H, Kageshita T. Br J Dermatol. 2006; 155: 582-585. Medline 16911285

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Takumi Hatayama, Nobuyuki Yamagishi Citation This paper should be referenced as such : Hatayama T, Yamagishi N . HSPH1 (heat shock 105kDa/110kDa protein 1). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HSPH1ID40891ch13q12.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 364 Atlas of Genetics and Cytogenetics in Oncology and Haematology

HSPD1 (Heat Shock 60kDa Protein 1) Identity Other names HSP60 HSP65 HuCHA60 Chaperonin 60kDa (CPN60) GROEL SPG13 Hugo HSPD1 Location 2q33.1 DNA/RNA Description The HSP60 gene contains 12 exons and 11 introns and was predicted to span over approximately 13 kb of the genomic DNA. The first exon is non-coding region. Transcription Two transcript variants encoding the same protein have been identified for HSP60 gene. This variant which was named HSP60s1 and HSP60s2 (s for short) comparing it to the much longer regular HSP60 gene. Pseudogene Twelve pseudogenes located on chromosome 3, 4, 5, 6, 8 and 12 have been associated with HSP60. Protein Description The HSP60 consists of 573 amino acids corresponding to a molecular weight of 61.05 kDa. The HSP60 proteins are ubiquitous abundant proteins of eubacterial genomes and also known as the Chaperonin. The Chapenonins divided into 2 subfamilies: Type I (HSP60/GROEL) and type II (TCP-1 ring complex). Type I are present in prokaryotes (eubacteria) and organelles (mitochondria and chloroplast). Type II are presents in archabacteria and in the eukaryotic cytosol. HSP60 family have the ring-shape oligomeric protein complex with a large central cavity, and composed of 14 proteins which organized into two 7-protein ring that are stacked on each other like double donut. This structure is reversible dissociate in the presence of Mg2+ and ATP, ATPase activity, and have role in folding and assembly of oligomeric protein structures. Expression HSP60 expression is ubiquitous in the pre-natal, different organ system, immune system, blood, epithelial tissue and cells. Localisation Mainly in the mitochondria, but growing body of evidence showed that there are also extra-mitochondrial such as in the cell surface, peroxisomes and the endoplasmic reticulum. Function Assisting mitochondrial protein folding, unfolding, and degradation. HSP60 also have anti-apoptosis and pro-apoptosis roles. Homology Up to now more than 150 homologues of HSP60 sequences with pair-wise similarity extending from 40-100% at the amino acid level. Among them: in rat (Rattus norvegicus), pufferfish (Fugu rubripes), zebrafish (Danio rerio), the nematode Caenorhabditis elegans and the mouse (Mus musculus). Mutations Germinal Not known in Homo sapiens. Somatic Hereditary spastic paraplegia (SPG13) is associated with a mutation in the HSP60

Atlas Genet Cytogenet Oncol Haematol 2007; 3 365 gene: The amino acid 72 Valine is changed to Isoleucin. In Sudden Death Infant Syndrome (SIDS), there are two mutations reported in the coding region of HSP60: N158S and G573A. Implicated in Entity Various carcinomas. Disease HSP60 reported to be over-expressed in exo-cervix cancer, colorectal cancer and prostate carcinoma. But down-regulate its expression in bladder cancer and lung carcinoma. Prognosis Controversy; worse prognosis in bladder cancer and acute myeloid leukemia. Others shows favorable prognosis, such as in ovarian cancer, osteo sarcoma and esophageal cancer. Oncogenesis The discrepancy of HSP60 expression and/or prognosis during carcinogenesis might be due to its pro- and anti-apoptotic roles in the cancer cells. The cytosolic and organellar forms of HSP60 might explain the anti- and pro-apoptotic roles.

Entity Diseases linked to deficiency of HSP60. Disease There is a few reports on HSP60 deficiency in human. Studies reported a patient with systemic mitochondrial encephalopathy, which had lower HSP60 concentration than normal person. Another HSP60 deficient patient presented with congenital lactic acidemia. In short chain acyl-CoA dehydrogenase, SCAD. HSP deficiency also reported in fibroblast derived from a patient with a fatal systemic mitochondrial disease leading to deficiency of multiple mitochondrial enzyme and mitochondrial abnormality.

Entity Autoimmune diseases. Note First clinical trials using HSP60 (peptide 277) has been tested in type-2 diabetes. Disease HSP60 have been implicated in T cell activation and cause inflammatory reaction. It involved in the pathogenesis of a number of autoimmune diseases in inflammatory conditions such as type-1 diabetes, juvenile chronic arthritis, atherosclerosis, Cohn disease, autoimmunity in women, rheumatoid arthritis, systemic lupus erythematodes, Sjogren syndrome and mix connective tissue diseases. External links Nomenclature Hugo HSPD1 GDB HSPD1 Entrez_Gene HSPD1 3329 heat shock 60kDa protein 1 (chaperonin) Cards Atlas HSPD1ID40888ch2q33 GeneCards HSPD1 Ensembl HSPD1 Genatlas HSPD1 GeneLynx HSPD1 eGenome HSPD1 euGene 3329 Genomic and cartography GoldenPath HSPD1 - 2q33.1 chr2:198059555-198072885 - 2q33.1 (hg18-Mar_2006) Ensembl HSPD1 - 2q33.1 [CytoView]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 366 NCBI Mapview OMIM Disease map [OMIM] HomoloGene HSPD1 Gene and transcription Genbank AU098504 [ ENTREZ ] Genbank BC002676 [ ENTREZ ] Genbank BC003030 [ ENTREZ ] Genbank BC047350 [ ENTREZ ] Genbank BC067082 [ ENTREZ ] RefSeq NM_002156 [ SRS ] NM_002156 [ ENTREZ ] RefSeq NM_199440 [ SRS ] NM_199440 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ] RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_005403 [ SRS ] NT_005403 [ ENTREZ ] RefSeq NW_921618 [ SRS ] NW_921618 [ ENTREZ ] AceView HSPD1 AceView - NCBI Unigene Hs.632539 [ SRS ] Hs.632539 [ NCBI ] HS632539 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P10809 [ SRS] P10809 [ EXPASY ] P10809 [ INTERPRO ] PS00296 CHAPERONINS_CPN60 [ SRS ] PS00296 CHAPERONINS_CPN60 [ Prosite Expasy ] Interpro IPR001844 Chaprnin_Cpn60 [ SRS ] IPR001844 Chaprnin_Cpn60 [ EBI ] Interpro IPR002423 Cpn60/TCP-1 [ SRS ] IPR002423 Cpn60/TCP-1 [ EBI ] Interpro IPR012723 GroEL [ SRS ] IPR012723 GroEL [ EBI ] Interpro IPR008950 GroEL-ATPase [ SRS ] IPR008950 GroEL-ATPase [ EBI ] CluSTr P10809 PF00118 Cpn60_TCP1 [ SRS ] PF00118 Cpn60_TCP1 [ Sanger ] pfam00118 [ Pfam NCBI-CDD ] Blocks P10809 HPRD P10809 Protein Interaction databases DIP P10809 IntAct P10809 Polymorphism : SNP, mutations, diseases OMIM 118190;605280 [ map ] GENECLINICS 118190;605280 SNP HSPD1 [dbSNP-NCBI] SNP NM_002156 [SNP-NCI] SNP NM_199440 [SNP-NCI] SNP HSPD1 [GeneSNPs - Utah] HSPD1] [HGBASE - SRS] HAPMAP HSPD1 [HAPMAP] COSMIC HSPD1 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family HSPD1 [UCSC Family Browser]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 367 Browser SOURCE NM_002156 SOURCE NM_199440 SMD Hs.632539 SAGE Hs.632539 GO nucleotide binding [Amigo] nucleotide binding GO ATP binding [Amigo] ATP binding GO ATP binding [Amigo] ATP binding GO cytoplasm [Amigo] cytoplasm GO mitochondrion [Amigo] mitochondrion GO protein folding [Amigo] protein folding GO protein folding [Amigo] protein folding GO response to unfolded protein [Amigo] response to unfolded protein protein import into mitochondrial matrix [Amigo] protein import into mitochondrial GO matrix GO regulation of apoptosis [Amigo] regulation of apoptosis GO unfolded protein binding [Amigo] unfolded protein binding GO unfolded protein binding [Amigo] unfolded protein binding GO chaperone binding [Amigo] chaperone binding PubGene HSPD1 Other databases Probes Probe HSPD1 Related clones (RZPD - Berlin) PubMed PubMed 117 Pubmed reference(s) in LocusLink Bibliography Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen. Jindal S, Dudani A K, Singh B, Harley C B, Gupta RS. Mol Cell Biol 1989; 9: 2279-2283. Medline 2568584

The mitochondrial chaperonin HSP60 is required for its own assembly. Cheng MY, Hartl FU, Horwich AL. Nature 1990; 348: 455-458. Medline 1978929

Nucleotide sequences and novel structural features of human and Chinese hamster HSP60 (chaperonin) gene families. Venner TJ, Singh B, Gupta RS. DNA Cell Biol 1990; 9: 545: 52. Medline 1980192

Antifolding activity of HSP60 couples protein import into the mitochondrial matrix with export to the intermembrane space. Koll H, Guiard B, Rassow J, Ostermann J, Horwich AL, Neupert W, Hartl FU. Cell 1992; 68: 1163-1175. Medline 1347713

Atlas Genet Cytogenet Oncol Haematol 2007; 3 368

Evolution of the chaperonin families (HSP60, HSP10 and TCP-1) of proteins and the origin of eukaryotic cells. Gupta RS. Mol Microbiol 1995; 15: 1-11. Medline 7752884

Genetic complexity of the human HSP60 gene. Pochon NA, Mach B. Int Immunol 1996; 8: 221-230. Medline 8671607

The genes encoding mammalian chaperonin60 and chaperonin10 are linked head-to-head and share a bidirectional promoter. Ryan MT, Herd SM, Sberna G, Samuel MM, Hoogenraad NJ, Hoj PB. Gene 1997; 196: 9-17. Medline 9322735

The HSP70 and HSP60 chaperone machine. Bukau B, Horwich AL. Cell 1998; 92: 351-366. Medline 9476895

Chaperone-mediated protein folding. Fink AL. Physiol Rev 1999; 70: 425-449. Medline 10221986

Mitochondrial-matrix proteins at unexpected locations: are they exported? Soltys BJ, Gupta RS. Trends Biochem Sci 1999; 24: 174-177. Medline 10322429

Chaperonins are cell-signaling proteins: the unfolding biology of molecular chaperones. Ranford JC, Coates AR, Henderson B. Expert Rev Mol Med 2000; 15: 1-17. Medline 14585136

Absence of prevalent sequence variations in the HSP60 and HSP10 chaperonin genes in 65 cases of Sudden Infant Death Syndrome (SIDS). Bross P., et al. Am J Hum Genet 2001; 69 (Suppl): pp 2193.

Unfolding the role of chaperones and chaperonins in human disease. Slavotinek AM, Biesecker LG. Trends Genet 2001; 17: 528-535. Medline 11525836

Heat shock proteins: the "Swiss Army Knife" vaccines against cancers and infectious agents. Srivastava PK, Amato RJ. Vaccine 2001; 19: 2590-2597. Medline 11257397

Chaperonin-mediated protein folding.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 369 Thirumalai D, Lorimer GH. Annu Rev Biophys Biomol Struct 2001; 30: 245-269. Medline 11340060

Hereditary Spastic Paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin HSP60. Hansen JJ, Durr A, Cournu-Rebeix I, Georgopoulos C, Ang D, Nielsen MN, Davoine CS, Brice A, Fontaine B, Gregersen N, Bross P. Am J Hum Genet 2002; 70: 1328-1332. Medline 11898127

Chaperonin60 unfolds its secrets of cellular communication. Maguire M, Coates AR, Henderson B. Cell Stress Chaperones 2002; 7: 317-329. Medline 12653476

Chaperonins in diseases: mechanisms, models, and treatment. Ranford JC, Henderson B. Mol Pathol 2002; 55: 209-213. Medline 12147708

Investigating a possible relation between the amino acid variation N158S of the human heat shock protein HSP60 and increased susceptibility to Sudden Infant Death Syndrome (SIDS). Teske A., et al. Am J Hum Genet 2002; 71 (Suppl): pp 503.

Genomic structure of the human mitochondrial chaperonin genes: HSP60 and HSP10 are localized head to head on separated by a bidirectional promoter. Hansen JJ, Bross P, Westergaard M, Nielsen MN, Eiberg H, Borglum AD, Mogensen J, Kristiansen K, Bolund L, Gregersen N. Hum Genet 2003; 112: 71-77. Medline 12483302

Mitochondrial chaperones in cancer: from molecular biology to clinical diagnostics. Czarnecka AM, Campanella C, Zummo G, Cappello F. Cancer Biol Ther 2006; 5: 714-720. Medline 16861898

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential. Bross P, Li Z, Hansen J, Hansen JJ, Nielsen MN, Corydon TJ, Georgopoulos C, Ang D, Lundemose JB, Niezen-Koning K, Eiberg H, Yang H, Kolvraa S, Bolund L, Gregersen N. J Hum Genet. 2007; 52: 56-65. Medline 17072495

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Ahmad Faried, Leri S Faried

Atlas Genet Cytogenet Oncol Haematol 2007; 3 370 Citation This paper should be referenced as such : Faried A, Faried LS . HSPD1 (Heat Shock 60kDa Protein 1). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HSPD1ID40888ch2q33.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 371 Atlas of Genetics and Cytogenetics in Oncology and Haematology

HIC1 (Hypermethylated in Cancer 1) Identity Other names ZBTB29 Hugo HIC1 Location 17p13.3. Close to the D17S5/D17S30/YNZ22 micro satellite marker which is a highly polymorphic variable number of tandem repeats (VNTR) marker. Aberrant Local_order hypermethylation in tumours of a cluster of methylation-sensitive NotI restriction sites surrounding this marker allowed the positional cloning of HIC1 in 1995. Telomere, OVCA1/DPH2L1, OVCA2, HIC1, KIAA0732,...... Centromere. Note OVCA1/DPH2L1 and OVCA2 are two tumour suppressor genes deleted in ovarian cancers. DNA/RNA Description The HIC1 gene extends approximately 15 Kbp and consists of four exons. The first three exons 1a, 1b and 1c are alternative. Note that exon 1a is included in exon 1c. The major transcripts are derived from alternative promoters associated with exon 1a and 1b. Exon 1c is conserved in rodent genomes (rat and mice) but transcripts containing it are very minor. The fourth exon, exon 2, contains the coding region and the 3' untranslated region. An in-frame upstream ATG initiation codon is also found in exon 1b. This upstream reading frame is conserved in mice. Transcription 3.0Kb mRNA. Pseudogene No known pseudogene. Protein Description 714 amino acids; around 80kDa; Transcription factor belonging to the BTB/POZ and Krüppel C2H2 zinc fingers family. There is no experimental evidence for the existence of a protein initiated by the upstream ATG (e.g. through the use of antipeptide specific antibodies). Expression Based on Northern Blots and RT-PCR experiments, HIC1 is widely expressed in various normal tissues. Localisation Nucleus. Localized on nuclear dots upon overexpression by transient transfection assays in COS-7 or HEK293 cells. In human primary fibroblats (WI38), the endogenous HIC1 proteins are localized in discrete nuclear structures called "HIC1 bodies". Function HIC1 is a transcriptional repressor belonging to the BTB/POZ and Krüppel C2H2 family (44 proteins in the ). HIC1 interacts with the corepressor CtBP through a conserved GLDLSKK motif in the central region. This central region also contains a SUMOylation site MK314HEP which is important for the transcriptional repression potential of HIC1. This K314 is also subject to a reversible acetylation/deacetylation implicating CBP/P300 and the NAD+ dependent class III deacetylase SIRT1. Homology HIC1 shares distant homology through the conserved BTB/POZ domain and C2H2 zinc fingers domain with several BTB/POZ transcriptional repressors. Mutations There are a number of reports highlighting differences in promoter methylation status in primary human tumours (breast, ovaries, prostate, .....) compared to matched

Atlas Genet Cytogenet Oncol Haematol 2007; 3 372 normal tissues, hence the name of the gene. Germinal No germinal coding sequence mutation have been described for HIC1. Somatic No somatic coding sequence mutations have been described for HIC1 with one exception. During the screening of a panel of 68 medulloblastomas using SSCP analyses, a 12-bp deletion in the second exon of HIC1 has been identified. This results in a deletion of 4 glycine residues in a stretch of 8 located just after the BTB/POZ domain. The other regions of the protein specially the downstream central region and the zinc fingers domain are not affected by this deletion. Implicated in Entity medulloblastomas, breast tumours, ovary tumours, prostate tumours Note (see above) Breakpoints Note No breakpoint in HIC1 identified so far. To be noted A paralog called HIC2, HRG22 or KIAA1020 is found on human chromosome 22. It is located in 22q11.2 in a region subject to translocations (BCRL-2 for Breakpoint Cluster Region-Like 2). But so far, there is no experimental evidence for a translocation implicating HRG22 or for its aberrant hypermethylation in tumours. External links Nomenclature Hugo HIC1 GDB HIC1 Entrez_Gene HIC1 3090 hypermethylated in cancer 1 Cards GeneCards HIC1 Ensembl HIC1 Genatlas HIC1 GeneLynx HIC1 eGenome HIC1 euGene 3090 Genomic and cartography GoldenPath HIC1 - 17p13.3. chr17:1904197-1906761 + 17p13.3 (hg18-Mar_2006) Ensembl HIC1 - 17p13.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene HIC1 Gene and transcription Genbank AJ550616 [ ENTREZ ] Genbank AJ583693 [ ENTREZ ] Genbank AJ583694 [ ENTREZ ] Genbank BC030208 [ ENTREZ ] Genbank BQ004706 [ ENTREZ ] RefSeq NM_001098202 [ SRS ] NM_001098202 [ ENTREZ ] RefSeq NM_006497 [ SRS ] NM_006497 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 373 RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010718 [ SRS ] NT_010718 [ ENTREZ ] RefSeq NW_926584 [ SRS ] NW_926584 [ ENTREZ ] AceView HIC1 AceView - NCBI Unigene Hs.634574 [ SRS ] Hs.634574 [ NCBI ] HS634574 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O95459 [ SRS] O95459 [ EXPASY ] O95459 [ INTERPRO ] PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 ZINC_FINGER_C2H2_1 [ Prosite Expasy ] PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 ZINC_FINGER_C2H2_2 [ Prosite Expasy ] Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] CluSTr O95459 Smart SM00355 ZnF_C2H2 [EMBL] Blocks O95459 HPRD O95459 Protein Interaction databases DIP O95459 IntAct O95459 Polymorphism : SNP, mutations, diseases OMIM 603825 [ map ] GENECLINICS 603825 SNP HIC1 [dbSNP-NCBI] SNP NM_001098202 [SNP-NCI] SNP NM_006497 [SNP-NCI] SNP HIC1 [GeneSNPs - Utah] HIC1] [HGBASE - SRS] HAPMAP HIC1 [HAPMAP] General knowledge Family HIC1 [UCSC Family Browser] Browser SOURCE NM_001098202 SOURCE NM_006497 SMD Hs.634574 SAGE Hs.634574 GO transcription factor activity [Amigo] transcription factor activity GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO cell cycle [Amigo] cell cycle GO multicellular organismal development [Amigo] multicellular organismal development GO zinc ion binding [Amigo] zinc ion binding

Atlas Genet Cytogenet Oncol Haematol 2007; 3 374 negative regulation of progression through cell cycle [Amigo] negative regulation of GO progression through cell cycle GO metal ion binding [Amigo] metal ion binding BIOCARTA Hypoxia and p53 in the Cardiovascular system [Genes] PubGene HIC1 Other databases Probes Probe HIC1 Related clones (RZPD - Berlin) PubMed PubMed 22 Pubmed reference(s) in LocusLink Bibliography p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Wales MM, Biel MA, el Deiry W, Nelkin BD, Issa JP, Cavenee WK, Kuerbitz SJ, Baylin SB. Nature Medicine. 1995; 1:570-577. Medline 7585125

Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: the case of HIC-1 and gammaFBP-B. Deltour S, Guerardel C, Leprince D. Proc Natl Acad Sci (U S A). 1999; 96: 14831-14836. Medline 10611298

Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome. Grimm C, Sporle R,.Schmid TE, Adler ID, Adamski J, Schughart K, Graw J. Hum Mol Genet. 1999; 8: 697-710 Medline 10072440

Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome. Carter MG, Johns MA, Zeng X, Zhou L, Zink MC, Mankowski JL, Donovan DM, Baylin SB. Hum. Mol. Genet. 2000; 9: 413-419. Medline 10655551

Characterization of HRG22, a human homologue of the putative tumor suppressor gene HIC1. Deltour S, Pinte S, Guerardel C, Leprince D. Biochem Biophys Res Commun. 2001; 287: 427-434. Medline 11554746

Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53. Guerardel C, Deltour S, Pinte S, Monte D, Begue A, Godwin AK, Leprince D. J Biol Chem. 2001; 276: 3078-3089. Medline 11073960

The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif. Deltour S, Pinte S, Guerardel C, Wasylyk B, Leprince D. Mol Cell Biol. 2002; 22: 4890-4901. Medline 12052894

Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of

Atlas Genet Cytogenet Oncol Haematol 2007; 3 375 malignant tumors. Chen WY, Zeng X., Carter M., Morrell CN, Chiu-Yen RW, Esteller M, Watkins DN, Herman JG, Mankowski JL, Baylin SB. Nature Genetics. 2003; 33:197-202. Medline 12539045

Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Chen W, Cooper TK, Zahnow CA, Overholtzer M, Zhao Z, Ladanyi M, Karp JE, Gokgoz N, Wunder JS, Andrulis IL, Levine AJ, Mankowski JL, Baylin SB. Cancer Cell. 2004; 6: 387-398. Medline 1548876

Identification of a second G-C-rich promoter conserved in the human, murine and rat tumor suppressor genes HIC1. Pinte S, Guerardel C, Deltour-Balerdi S, Godwin AK, Leprince D. Oncogene. 2004; 23: 4023-4031. Medline 15007385

The tumor suppressor gene HIC1 (hypermethylated in cancer 1) is a sequence-specific transcriptional repressor: definition of its consensus binding sequence and analysis of its DNA binding and repressive properties. Pinte S, Stankovic-Valentin N, Deltour S, Rood BR, Guerardel C, Leprince D. J Biol Chem. 2004; 279: 38313-38324. Medline 15231840

HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB. Cell. 2005; 123: 437-448. Medline 16269335

Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1. Britschgi C, Rizzi M, GrobTJ, Tschan MP, Hugli B, Reddy VA, Andres AC, Torbett BE, Tobler A, Fey MF. Oncogene. 2006; 25: 2030-2039. Medline 16301995

A L225A substitution in the human tumour suppressor HIC1 abolishes its interaction with the corepressor CtBP. Stankovic-Valentin N, Verger A, Deltour-Balerdi S, Quinlan KG, Crossley M, Leprince D. Febs J. 2006; 273: 2879-2890. Medline 16762039

HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies. Valenta T, Lukas J, Doubravska L, Fafilek B, Korinek V. Embo J. 2006; 25: 2326-2337. Medline 16724116

An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKxEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Stankovic-Valentin N, Deltour S, Seeler J, Pinte S, Vergoten G, Guérardel C, Dejean A, Leprince D. Mol Cell Biol. 2007; 27: in press. Medline 17213307

Atlas Genet Cytogenet Oncol Haematol 2007; 3 376 Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex. Zhang Q, Wang SH, Fleuriel C, Leprince D, Rocheleau JV, Piston DW, Goodman RH. Proc Natl Acad Sci (U S A). 2007; 104:829-33. Medline 17213307

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Dominique Leprince Citation This paper should be referenced as such : Leprince D . HIC1 (Hypermethylated in Cancer 1). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HIC1ID40819ch17p13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 377 Atlas of Genetics and Cytogenetics in Oncology and Haematology

FLCN (folliculin gene) Identity Other names BHD FLCL Folliculin Hugo FLCN Location 17p11.2 Note Putative tumor suppressor gene DNA/RNA

Description The FLCN/BHD gene consists of a 3717 nt mRNA (using NM_144997 derived from BQ423946 and AF517523, the coding sequence extends from nt499 to nt2238) and contains 14 coding exons. The initiation codon is located within exon 4. Transcription Northern blot analysis revealed a 3.8 kb FLCN/BHD mRNA transcript expressed in most tissues Alternate splicing of FLCN/BHD results in two transcript variants encoding two different isoforms. Transcript 1 is the full-length isoform. Transcript 2 has a shorter and distinct C-terminus from Transcript 1. Protein Description The BHD protein, folliculin (FLCN), consists of 579 amino acids with a central glutamic acid-rich coiled-coil domain, one N-glycosylation site and three myristoylation sites, and an estimated molecular weight of 64.5 kDa. Expression expressed in most major adult tissues, including kidney, lung and skin, which are involved in the BHD phenotype. Localisation Epitope-tagged FLCN expressed in HEK293 cells localized in both the nucleus and cytoplasm by fluorescence in situ hybridization.. Function FLCN is a novel protein, with no characteristic domains to suggest function. Coimmunoprecipitation studies have identified a novel folliculin-binding partner, FNIP1, which also interacts with 5¹AMP-activated protein kinase (AMPK), a key molecule for energy sensing and a negative regulator of mTOR (mammalian target of rapamycin). FLCN exists in phosphorylated forms, which are enhanced by FNIP1 overexpression, and suppressed by inhibitors of mTOR signaling including rapamycin and amino acid starvation, and by an AMPK inhibitor, Compound C. These data suggest that FLCN and its interacting partner, FNIP1, may be involved in energy and nutrient-sensing through the AMPK and mTOR signaling pathways. Using a genetic approach in Drosophila, RNA interference studies to decrease expression of the fly BHD homolog, DBHD, have established a requirement for DBHD in male germline stem cell maintenance in the fly testis. Further genetic studies to examine the interaction between DBHD and the JAK/STAT pathway, which is necessary for germline stem cell self-renewal, suggested that DBHD may regulate

Atlas Genet Cytogenet Oncol Haematol 2007; 3 378 maintenance of germline stem cells downstream of or in parallel with the JAK/STAT and Dpp(a TGFbeta family member) signaling pathways. Thus the work with the Drosophila homolog of FLCN/BHD supports a potential role for DBHD in stem cell maintenance and raises the possibility that dysregulation of FLCN in human tumors may result from aberrant modulation of stem cells. Homology Folliculin shows no strong homology to any known proteins but is evolutionarily conserved, and orthologs have been identified in chimpanzee, dog, cow, rat, mouse, red jungle fowl, frog, fly, and worm. Mutations Germinal All FLCN/BHD germline mutations identified in Birt-Hogg-Dubé (BHD) patients are predicted to truncate the mutant protein, including frameshift (insertions/deletions), nonsense and splice-site mutations. To date, no missense germline mutations have been identified. The mutation detection rate in BHD families is about 84%. Mutations are located along the entire length of the coding region, with no genotype-phenotype correlations noted between type of mutation, location within the gene and phenotypic disease manifestations (BHD skin lesions, lung cysts/spontaneous pneumothorax and renal tumors). The most frequent mutation found in the germline of BHD patients is the insertion or deletion of a cytosine in a C8 tract located in exon 11, predicted to cause a frameshift and prematurely truncate the mutant protein. This hot spot mutation occurs in about half of all BHD patients. Among BHD patients with the exon 11 mutation, significantly fewer renal tumors developed in patients with the C-deletion than those with the C-insertion mutation. Germline FLCN/BHD mutations have been reported in primary spontaneous pneumothorax (PSP) families with nearly 100% penetrance in family members in which lung blebs or bullae indicated affected status. The PSP-associated mutations, including 2 nonsense and one 4-bp deletion, are predicted to prematurely truncate the protein and are located in exons 9, 12 and 4, respectively. Somatic FLCN/BHD somatic mutations have been found at only a very low frequency (0-10%) in sporadic renal tumors and therefore, may not represent a major mechanism for the development of sporadic renal carcinoma. Loss of 17p DNA including p53 (36%) or partial methylation (28%) of the FLCN/BHD promoter were reported in sporadic renal carcinomas with various histologies. Mutations have been identified in the mutational hot spot in exon 11 of the FLCN/BHD gene in other tumor types exhibiting microsatellite instability, including colorectal carcinoma (20%), endometrial carcinoma (12%) and gastric carcinoma (16%). Implicated in Entity Birt-Hogg-Dubé(BHD) syndrome Disease Birt-Hogg-Dubé(BHD) syndrome is an inherited autosomal dominant genodermatosis characterized by benign tumors of the hair follicle (fibrofolliculoma), lung cysts, spontaneous pneumothorax and renal neoplasia. Colon polyps or colon cancer may be part of the disease manifestations in some BHD cohorts although no statistically significant association was found. BHD syndrome is caused by germline mutations in the FLCN/BHD gene. Any or all of these phenotypic features may develop in a BHD patient; the phenotype is variable within and among BHD families inheriting the identical FLCN/BHD mutation (i.e., C-insertion/deletion in exon 11). Prognosis BHD is a rare disorder occurring in about 1/200,000 individuals. The BHD skin lesions, which develop after puberty (above 25 years of age) are highly penetrant (above 85%) and may be disfiguring, but they are benign and have no health consequences. Lung cysts detected by thoracic CT scan are very frequent (above 85%) in BHD patients. Episodes of spontaneous pneumothorax in BHD patients occur with a higher frequency before the age of 40, and repeat episodes cease after surgical intervention. The risk for developing renal neoplasia is about 7-fold higher for BHD mutation carriers than for their unaffected siblings. Most commonly, chromophobe renal carcinoma (34%) and oncocytic hybrid tumors (50%), develop in about half of BHD families with an average age at diagnosis of 48-50 and a male/female ratio of 2:1. Tumors may develop bilaterally with multiple foci or unilaterally with a single focus, and variable

Atlas Genet Cytogenet Oncol Haematol 2007; 3 379 tumor histology may be seen in a single patient¹s kidney and among BHD family members carrying the same FLCN/BHD mutation. Oncogenesis Patients with BHD syndrome are at a higher risk for the development of chromophobe renal carcinoma, oncocytic hybrid renal tumors and clear cell renal carcinoma, which may be aggressive and metastatic. Renal oncocytosis, which are small clusters of cells resembling those found in the larger hybrid tumors, have been found scattered throughout the kidney of a majority of BHD patients, suggesting that the entire renal parenchyma may be at risk for tumor development. Second hit somatic mutations in the remaining wild type copy of the FLCN/BHD gene have been identified in renal tumors from BHD patients with germline mutations and may contribute to the progression of renal oncocytosis to renal neoplasia (see below).

Entity Primary Spontaneous Pneumothorax (PSP) Disease Primary spontaneous pneumothorax is a condition in which air is present in the pleural space without a precipitating event that results in the secondary partial or complete collapse of the lung. FLCN/BHD mutations have been found associated with inherited autosomal dominant primary spontaneous pneumothorax (PSP) in some PSP families. In these families PSP was the only phenotypic feature and the mutation was 100% penetrant with lung bullae. To be noted Animal models of BHD: A germline single nucleotide insertion in the first coding exon of the rat Bhd ortholog was found in the Nihon rat, an established animal model of renal carcinoma, which develops renal tumors by 8 weeks of age. A germline mutation in the canine Bhd ortholog, which changes a conserved histidine to arginine (H255R), gives rise to RCND (renal cystadenoma nodular dermatofibroma) in the German Shepherd dog with a renal tumor and skin nodule phenotype. Tumor suppressor role for FLCN/BHD: Somatic mutations in the wild type copy of the FLCN/BHD gene or loss of heterozygosity at 17p11.2 have been identified in a majority of renal tumors from BHD patients who inherit germline mutations, suggesting that FLCN/BHD may act as a tumor suppressor gene. Tumors from a single BHD patient have different second mutations or LOH, but within the same tumor, even within regions with different histologies, the same second mutation was observed, suggesting that multiple tumors arise from independent, clonal events initiated by the second hit. Haploinsufficiency, however, may be sufficient for the development of the benign hair follicle tumors (fibrofolliculomas), because the wild type copy of the FLCN/BHD gene is retained in microdissected tissue from these skin lesions. External links Nomenclature Hugo FLCN GDB FLCN Entrez_Gene FLCN 201163 folliculin Cards Atlas FLCNID789ch17p11 GeneCards FLCN Ensembl FLCN Genatlas FLCN GeneLynx FLCN eGenome FLCN euGene 201163 Genomic and cartography

Atlas Genet Cytogenet Oncol Haematol 2007; 3 380 GoldenPath FLCN - 17p11.2 chr17:17065211-17081221 - 17p11.2 (hg18-Mar_2006) Ensembl FLCN - 17p11.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene FLCN Gene and transcription Genbank AF517523 [ ENTREZ ] Genbank AK127912 [ ENTREZ ] Genbank BC015687 [ ENTREZ ] Genbank BC015725 [ ENTREZ ] Genbank BQ423946 [ ENTREZ ] RefSeq NM_144606 [ SRS ] NM_144606 [ ENTREZ ] RefSeq NM_144997 [ SRS ] NM_144997 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010718 [ SRS ] NT_010718 [ ENTREZ ] RefSeq NW_926628 [ SRS ] NW_926628 [ ENTREZ ] AceView FLCN AceView - NCBI Unigene Hs.513975 [ SRS ] Hs.513975 [ NCBI ] HS513975 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q8NFG4 [ SRS] Q8NFG4 [ EXPASY ] Q8NFG4 [ INTERPRO ] CluSTr Q8NFG4 Blocks Q8NFG4 HPRD Q8NFG4 Protein Interaction databases DIP Q8NFG4 IntAct Q8NFG4 Polymorphism : SNP, mutations, diseases OMIM 114500;135150;144700;173600;607273 [ map ] GENECLINICS 114500;135150;144700;173600;607273 SNP FLCN [dbSNP-NCBI] SNP NM_144606 [SNP-NCI] SNP NM_144997 [SNP-NCI] SNP FLCN [GeneSNPs - Utah] FLCN] [HGBASE - SRS] HAPMAP FLCN [HAPMAP] General knowledge Family FLCN [UCSC Family Browser] Browser SOURCE NM_144606 SOURCE NM_144997 SMD Hs.513975 SAGE Hs.513975 GO cell cycle [Amigo] cell cycle GO negative regulation of progression through cell cycle [Amigo] negative regulation of

Atlas Genet Cytogenet Oncol Haematol 2007; 3 381 progression through cell cycle PubGene FLCN Other databases Probes Probe FLCN Related clones (RZPD - Berlin) PubMed PubMed 19 Pubmed reference(s) in LocusLink Bibliography Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjold M, Teh BT. Oncogene. 2001; 20: 5239-5242. Medline 11526515

Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Schmidt LS, Warren MB, Nickerson ML, Weirich G, Matrosova V, Toro JR, Turner ML, Duray P, Merino M, Hewitt S, Pavlovich CP, Glenn G, Greenberg CR, Linehan WM, Zbar B. Am J Hum Genet. 2001; 69: 876-882. Medline 11533913

Clinical and genetic studies of Birt-Hogg-Dubé syndrome. Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, Binet O, Lambert D, Friedel J, Levy R, Ferlicot S, Wolkenstein P, Hammel P. Bergerheim U, Hedblad MA, Bradley M, Teh BT, Nordenskjold M, Richard S. J Med Genet. 2002; 39: 906-912. Medline 12471204

Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS. Cancer Cell. 2002; 2: 157-164. Medline 12204536

Renal tumors in the Birt-Hogg-Dubé syndrome. Pavlovich CP, Walther MW, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ. Am J Surg Path. 2002; 26: 1542-1552. Medline 12459621

Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM. Cancer Epidemiol. Biomarkers Prev. 2002; 11: 393-400. Medline 11927500

Analysis of the Birt-Hogg-Dube (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. da Silva NF, Gentle D, Hesson LB, Morton DG, Latif F, Maher ER. J Med Genet. 2003; 40: 820-824. Medline 14627671

Atlas Genet Cytogenet Oncol Haematol 2007; 3 382

Alterations of the Birt-Hogg-Dube gene (BHD) in sporadic colorectal tumours. Kahnoski K, Khoo SK, Nassif NT, Chen J, Lobo GP, Segelov E, Teh BT. J Med Genet. 2003; 40: 511-515. Medline 12843323

Inactivation of BHD in sporadic renal tumors. Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, Ludlow J, Knapp R, Giraud S, Richard S, Nordenskjold M, Teh BT. Cancer Res. 2003; 63: 4583-4587. Medline 12907635

A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Lingaas F, Comstock KE, Kirkness EF, Sorensen A, Aarskaug T, Hitte C, Nickerson ML, Moe L, Schmidt LS, Thomas R, Breen M, Galibert F, Zbar B, Ostrander EA. Hum Mol Genet. 2003; 12: 3043-3053. Medline 14532326

Mutations of the Birt-Hogg-Dube (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability. Shin JH, Shin YK, Ku JL, Jeong SY, Hong SH, Park SY, Kim WH, Park JG. J Med Genet. 2003; 40: 364-367. Medline 12746401

Lack of mutation of the folliculin gene in sporadic chromophobe renal cell carcinoma and renal oncocytoma. Nagy A, Zoubakov D, Stupar Z, Kovacs G. Int J Cancer. 2004; 109: 472-475. Medline 14961590

A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer. Okimoto K, Sakurai J, Kobayashi T, Mitani H, Hirayama Y, Nickerson ML, Warren MB, Zbar B, Schmidt LS, Hino O. Proc Natl Acad Sci U S A. 2004; 101: 2023-2027. Medline 14769940

Birt-Hogg-Dube syndrome, a genodermatosis that increases risk for renal carcinoma. Schmidt LS. Curr Mol Med. 2004; 4: 877-885. (REVIEW.) Medline 15579035

Expression of Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues. Warren MB, Torres-Cabala CA, Turner ML, Merino MJ, Matrosova VY, Nickerson ML, Ma W, Linehan WM, Zbar B, Schmidt LS. Mod Pathol. 2004; 17: 998-1011. Medline 15143337

Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Graham RB, Nolasco M, Peterlin B, Garcia CK. Am J Respir Crit Care Med. 2005; 172: 39-44. Medline 15805188

Atlas Genet Cytogenet Oncol Haematol 2007; 3 383

A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly inherited spontaneous pneumothorax. Painter JN, Tapanainen H, Somer M, Tukiainen P, Aittomaki K. Am J Hum Genet. 2005; 76: 522-527. Medline 15657874

Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. Pavlovich CP, Grubb RL 3rd, Hurley K, Glenn GM, Toro J, Schmidt LS, Torres-Cabala C, Merino MJ, Zbar B, Choyke P, Walther MM, Linehan WM. J Urol. 2005; 173: 1482-1486.

Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, Linehan WM. Am J Hum Genet. 2005; 76: 1023-1033. Medline 15852235

High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dube-associated renal tumors. Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, Merino MJ, Walther MM, Zbar B, Linehan WM. J Natl Cancer Inst. 2005; 97: 931-935. Medline 15956655

Birt-Hogg-Dube syndrome: clinicopathologic findings and genetic alterations. Adley BP, Smith ND, Nayar R, Yang XJ. Arch Pathol Lab Med. 2006; 130: 1865-1870. (REVIEW.) Medline 17149965

Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, Zbar B. Proc Natl Acad Sci U S A. 2006; 103: 15552-15557. Medline 17028174

A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt- Hogg-Dube syndrome. Bessis D, Giraud S, Richard S. Br J Dermatol. 2006; 155: 1067-1069. Medline 17034545

Birt-Hogg-Dube gene mutations in human endometrial carcinomas with microsatellite instability. Fujii H, Jiang W, Matsumoto T, Miyai K, Sashara K, Ohtsuji N, Hino O. J Pathol. 2006; 209: 328-335. Medline 16691634

Birt-Hogg-Dube (BHD) gene mutations in human gastric cancer with high frequency microsatellite instability. Jiang W, Fujii H, Matsumoto T, Ohtsuji N, Tsurumaru M, Hino O. Cancer Lett. 2006; [Epub ahead of print]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 384 Medline 16870330

The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK- STAT and Dpp signaling pathways in regulating male germline stem cell maintenance. Singh SR, Zhen W, Zheng Z, Wang H, Oh SW, Liu W, Zbar B, Schmidt LS, Hou SX. Oncogene. 2006; 25: 5933-5941. Medline 16636660

Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma. Gad S, Lefevre SH, Khoo SK, Giraud S, Vieillefond A, Vasiliu V, Ferlicot S, Molinie V, Denoux Y, Thiounn N, Chretien Y, Mejean A, Zerbib M, Benoit G, Herve JM, Allegre G, Bressac-de Paillerets B, Teh BT, Richard S. Br J Cancer. 2007; 96: 336-340. Medline 17028174

Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dube patients. van Steensel MA, Verstraeten VL, Frank J, Kelleners-Smeets NW, Poblete-Gutierrez P, Marcus- Soekarman D, Bladergroen RS, Steijlen PM, van Geel M. J Invest Dermatol. 2007; 127: 588-593. Medline 17124507

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Laura S Schmidt Citation This paper should be referenced as such : Schmidt LS . FLCN (folliculin gene). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/FLCNID789ch17p11.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 385 Atlas of Genetics and Cytogenetics in Oncology and Haematology

ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2) Identity Other names Autotaxin ATX NPP2 PD1alpha lysophospholipase D PDNP2 Hugo ENPP2 Location 8q24.12 Telomeric to NOV (nephroblastoma overxpressed gene), centromeric to TAF2; Local_order colocalized with pseudogene CYCSP23. DNA/RNA Note mRNA length 3276 or 3120 bp, depending upon alternate splicing.

ENPP2 Gene: Intron-exon organization of ENPP2.

Description The ENPP2 gene is 81,754 bp in length and is composed of 26 exons. Part of exon 1 and 26 are untranslated (UTR); translation extends from the remainder of exon 1 through the proximal portion of exon 26; however, there is a 152 bp exon (exon 12) that is alternatively spliced and is included primarily in neurally derived tissues. Transcriptio The mRNA for ENPP2 is 3276 bp with exon 12 and 3120 bp without it. The ENPP2 n promoter is reported to have four SP1 sites as well as binding sites for NFAT and NF- kappaB but no TATA or CAAT boxes. The only transcription factor that has been proven to increase ENPP2 protein expression is NFATC2/NFAT1, after release of alpha6beta4 from hemidesmosomes in a breast cancer cell line. A number of growth factors have been found to stimulate ENPP2 protein expression, while several inflammatory cytokines have been reported to inhibit expression. Pseudogene CYCSP23 Protein

ENPP2 Protein (NPP2/ATX): Organization of domains and other critical elements within ENPP2.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 386 Description The ENPP2 protein, NPP2 or ATX, is an N-glycolsylated member of the ecto- nucleotide pyrophosphatase and phosphodiesterase (NPP) family of proteins. The NPP2 precursor contains 915 amino acids, 105.2 KDa; and an alternately spliced variant is 863 amino acids, 99.0 KDa. The amino terminal signal peptide sequence is cleaved at a signal peptidase site between G27 and F28 to yield a secreted protein that contains 888/836 amino acids, 102.3/96.9 KDa. NPP2 contains up to 3 ASN- linked glycosylation sites that appear to be required for secretion as well as for stabilization of its active conformation. Expression NPP2 is expressed in many tissues during development, but it is critical for blood vessel maturation and neurogenesis. Certain inflammatory cytokines and the tumor suppressor CST6 downregulate ENPP2 expression, and some of the NPP2 products exert a negative feedback on its expression. Conversely, a number of growth factors as well as EBV infection (in Hodgkin's lymphoma) upregulate ENPP2 expression. Disruption of hemidesmosomes in breast cancer cells releases alpha6beta4, which initiates a signaling cascade that culminates in the activation of the transcription factor NFAT1, which binds to the ENPP2 promoter to upregulate protein expression. Upregulation of ENPP2 has been reported in a number of aggressive tumors, including glioblastoma, undifferentiated anaplastic thyroid carcinoma, invasive breast carcinoma, and metastatic hepatocellular carcinoma. In adults, NPP2 is the major source of serum and plasma lysophospholipase D activity. It is also highly expressed in brain, kidney, liver, ovary, small intestine, and placenta, and is present in many other tissues. Function NPP2 is a Type 2 nucleotide pyrophosphatase and phosphodiesterase that also has ATPase activity. In addition, NPP2 is the major source of serum and plasma lysophospholipase D activity, hydrolyzing lysophosphatidylcholine into lysophosphatidic acid as well as cyclic phosphatidic acid. NPP2 also hydrolyzes sphingosylphosphorylcholine into sphingosine-1-phosphate; however, NPP2 is not a major source of sphingosine-1-phosphate in plasma. The production of lysophosphatidic acid is thought to account for many of the physiological and pathological roles of ENPP2. Both enzymatic activities of NPP2 share a common catalytic domain. Like other members of the NPP family, NPP2 is a metallo-enzyme with binding sites for 2 metal atoms coordinated by three critical histidines (H316, H360, and H475) and associated aspartates (D172, D312, and D359). T210 is nucleotidylated during the nucleotide pyrophosphatase/phosphodiesterase reaction and is essential for hydrolysis of substrate during the lysophospholipase D reaction as well. Homology NPP2 is a member of the nucleotide pyrophosphatase and phosphodiesterase family, which includes ENPP1 (PC1) and ENPP3 (B10). Although the catalytic domain is highly conserved within this family of proteins, only NPP2 possesses lysophospholipase D activity. Mutations Note There are a number of single nucleotide polymorphisms (SNPs) that have been reported within the ENPP2 gene but none are yet reported to be associated with altered phenotype. However, knockout of ENPP2 is lethal in mice (approximately E12), therefore mutations associated with loss of function might be lethal. Implicated in Entity Various cancers Disease Overexpression of the ENPP2 protein has been associated with tumor cell motility and invasion, tumor growth and metastasis, and blood vessel formation. Prognosis ENPP2 is over-expressed in poorly differentiated non-small cell lung carcinomas and invasive and metastatic hepatocellular carcinoma. In thyroid carcinomas, ENPP2 expression was found to be higher in undifferentiated anaplastic thyroid carcinoma cell lines and tissues than in follicular thyroid carcinomas or goiters. When glioblastoma multiforme cells were collected from tumor cores vs. areas of white matter invasion, ENPP2 was found to be overexpressed predominantly at the invasive front.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 387 Oncogenesis Upregulation of NPP2 expression appears to be associated with cancer progression rather than with oncogenesis. Transfection of ENPP2 cDNA into mouse fibroblast cell lines (NIH3T3 clone7) did not result in tumorigenic cell lines, but transfection into Ras- transformed fibroblasts resulted in rapidly growing, hematogenous, highly metastatic tumors. NPP2 expression was found in Hodgkin's lymphoma cells as well as in CD30+ anaplastic large-cell lymphomas. In the Hodgkin's lymphomas , EBV infection was correlated to induction of ENPP2 expression (P = 0.006). Transfection of the tumor suppressor CST6 into MDA-MB-435 cells resulted in down- regulation of ENPP2. In contrast, down regulation of ENPP2 by specific siRNAs resulted in down-regulation of the tumor suppressors, thrombospondin-1 and thrombospondin-2 (THBS1 and THBS2, respectively).

Entity Diabetes Disease NPP2 expression is highly upregulated during adipocyte differentiation and its product, lysophosphatidic acid, stimulates proliferation in preadipocytes. In genetically obese, diabetic mice, NPP2 expression was increased in adipose tissue compared to their lean siblings. This is a possible model for type 2 diabetes, which has a strong genetic component. External links Nomenclature Hugo ENPP2 GDB ENPP2 Entrez_Gene ENPP2 5168 ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin) Cards GeneCards ENPP2 Ensembl ENPP2 Genatlas ENPP2 GeneLynx ENPP2 eGenome ENPP2 euGene 5168 Genomic and cartography GoldenPath ENPP2 - 8q24.12 chr8:120638500-120720287 - 8q24.1 (hg18-Mar_2006) Ensembl ENPP2 - 8q24.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene ENPP2 Gene and transcription Genbank AK124910 [ ENTREZ ] Genbank AK130313 [ ENTREZ ] Genbank AL544867 [ ENTREZ ] Genbank BC034961 [ ENTREZ ] Genbank BQ365938 [ ENTREZ ] RefSeq NM_001040092 [ SRS ] NM_001040092 [ ENTREZ ] RefSeq NM_006209 [ SRS ] NM_006209 [ ENTREZ ] RefSeq AC_000051 [ SRS ] AC_000051 [ ENTREZ ] RefSeq NC_000008 [ SRS ] NC_000008 [ ENTREZ ] RefSeq NT_008046 [ SRS ] NT_008046 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 388 RefSeq NW_923984 [ SRS ] NW_923984 [ ENTREZ ] AceView ENPP2 AceView - NCBI Unigene Hs.190977 [ SRS ] Hs.190977 [ NCBI ] HS190977 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q13822 [ SRS] Q13822 [ EXPASY ] Q13822 [ INTERPRO ] Prosite PS00524 SMB_1 [ SRS ] PS00524 SMB_1 [ Expasy ] Prosite PS50958 SMB_2 [ SRS ] PS50958 SMB_2 [ Expasy ] Interpro IPR001604 Endonuclease [ SRS ] IPR001604 Endonuclease [ EBI ] Interpro IPR002591 Phosphodiest [ SRS ] IPR002591 Phosphodiest [ EBI ] Interpro IPR001212 Somatomedin_B [ SRS ] IPR001212 Somatomedin_B [ EBI ] CluSTr Q13822 PF01223 Endonuclease_NS [ SRS ] PF01223 Endonuclease_NS [ Sanger Pfam ] pfam01223 [ NCBI-CDD ] PF01663 Phosphodiest [ SRS ] PF01663 Phosphodiest [ Sanger ] pfam01663 [ Pfam NCBI-CDD ] PF01033 Somatomedin_B [ SRS ] PF01033 Somatomedin_B [ Sanger Pfam ] pfam01033 [ NCBI-CDD ] Smart SM00477 NUC [EMBL] Smart SM00201 SO [EMBL] Blocks Q13822 HPRD Q13822 Protein Interaction databases DIP Q13822 IntAct Q13822 Polymorphism : SNP, mutations, diseases OMIM 601060 [ map ] GENECLINICS 601060 SNP ENPP2 [dbSNP-NCBI] SNP NM_001040092 [SNP-NCI] SNP NM_006209 [SNP-NCI] SNP ENPP2 [GeneSNPs - Utah] ENPP2] [HGBASE - SRS] HAPMAP ENPP2 [HAPMAP] General knowledge Family ENPP2 [UCSC Family Browser] Browser SOURCE NM_001040092 SOURCE NM_006209 SMD Hs.190977 SAGE Hs.190977 3.1.4.39 [ Enzyme-SRS ] 3.1.4.39 [ Brenda-SRS ] 3.1.4.39 [ KEGG ] 3.1.4.39 [ Enzyme WIT ] GO nucleic acid binding [Amigo] nucleic acid binding GO endonuclease activity [Amigo] endonuclease activity GO phosphodiesterase I activity [Amigo] phosphodiesterase I activity GO nucleotide diphosphatase activity [Amigo] nucleotide diphosphatase activity

Atlas Genet Cytogenet Oncol Haematol 2007; 3 389 GO plasma membrane [Amigo] plasma membrane GO integral to plasma membrane [Amigo] integral to plasma membrane GO phosphate metabolic process [Amigo] phosphate metabolic process GO cell motility [Amigo] cell motility GO chemotaxis [Amigo] chemotaxis G-protein coupled receptor protein signaling pathway [Amigo] G-protein coupled GO receptor protein signaling pathway GO transcription factor binding [Amigo] transcription factor binding GO metabolic process [Amigo] metabolic process GO nucleotide metabolic process [Amigo] nucleotide metabolic process GO lipid catabolic process [Amigo] lipid catabolic process GO hydrolase activity [Amigo] hydrolase activity GO metal ion binding [Amigo] metal ion binding alkylglycerophosphoethanolamine phosphodiesterase activity GO [Amigo] alkylglycerophosphoethanolamine phosphodiesterase activity KEGG Purine KEGG Starch and Sucrose Metabolism KEGG Riboflavin Metabolism KEGG Nicotinate and Nicotinamide Metabolism KEGG Pantothenate and CoA Biosynthesis PubGene ENPP2 Other databases Probes Probe ENPP2 Related clones (RZPD - Berlin) PubMed PubMed 31 Pubmed reference(s) in LocusLink Bibliography Identification, purification, and partial sequence analysis of autotaxin, a novel motility- stimulating protein. Stracke ML, Krutzsch HC, Unsworth EJ, Arestad A, Cioce V, Schiffmann E, Liotta LA. J Biol Chem. 1992; 267: 2524-2529. Medline 1733949 cDNA cloning of the human tumor motility-stimulating protein, autotaxin, reveals a homology with phosphodiesterases. Murata J, Lee HY, Clair T, Krutzsch HC, Arestad AA, Sobel ME, Liotta LA, Stracke ML. J Biol Chem. 1994; 269: 30479-30484. Medline 7982964

Molecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2). Kawagoe H, Soma O, Goji J, Nishimura N, Narita M, Inazawa J, Nakamura H, Sano K. Genomics. 1995; 30: 380-384. Medline 8586446

Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin. Lee HY, Clair T, Mulvaney PT, Woodhouse EC, Aznavoorian S, Liotta LA, Stracke ML. J Biol Chem. 1996; 271: 24408-24412.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 390 Medline 8798697

Cloning, chromosomal localization, and tissue expression of autotaxin from human teratocarcinoma cells. Lee HY, Murata J, Clair T, Polymeropoulos MH, Torres R, Manrow RE, Liotta LA, Stracke ML. Biochem Biophys Res Commun. 1996; 218: 714-719. Medline 8579579

Autotaxin is an exoenzyme possessing 5'-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities. Clair T, Lee HY, Liotta LA, Stracke ML. J Biol Chem. 1997; 272: 996-1001. Medline 8995394

Expression and transcriptional regulation of the PD-Ialpha/autotaxin gene in neuroblastoma. Kawagoe H, Stracke ML, Nakamura H, Sano K. Cancer Res. 1997; 236: 449-454. Medline 9192834

Bmp-2 downstream targets in mesenchymal development identified by subtractive cloning from recombinant mesenchymal progenitors (C3H10T1/2). Bachner D, Ahrens M, Schroder D, Hoffmann A, Lauber J, Betat N, Steinert P, Flohe L, Gross G. Dev Dyn. 1998; 213: 398-411. Medline 9853961

Developmental expression analysis of murine autotaxin (ATX). Bachner D, Ahrens M, Betat N, Schroder D, Gross G. Mech Dev. 1999; 84: 121-125. Medline 1047312

Autotaxin expression in non-small-cell lung cancer. Yang Y, Mou Lj, Liu N, Tsao MS. Am J Respir Cell Mol Biol. 1999; 21: 216-222. Medline 10423404

Expression of autotaxin mRNA in human hepatocellular carcinoma. Zhang G, Zhao Z, Xu S, Ni L, Wang X. Chin Med J (Engl). 1999; 112: 330-332. Medline 11593532

Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic potential of ras- transformed cells. Nam SW, Clair T, Campo CK, Lee HY, Liotta LA, Stracke ML. Oncogene. 2000; 19: 241-247. Medline 10645002

Structural and catalytic similarities between nucleotide pyrophosphatases/phosphodiesterases and alkaline phosphatases. Gijsbers R, Ceulemans H, Stalmans W, Bollen M. J Biol Chem. 2001; 276: 1361-1368. Medline 11027689

Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor. Nam SW, Clair T, Kim YS, McMarlin A, Schiffmann E, Liotta LA, Stracke ML.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 391 Cancer Res. 2001; 61: 6938-6944. Medline 11559573

Autotaxin promotes motility via G protein-coupled phosphoinositide 3-kinase gamma in human melanoma cells. Lee HY, Bae GU, Jung ID, Lee JS, Kim YK, Noh SH, Stracke ML, Park CG, Lee HW, Han JW. FEBS Lett. 2002; 515: 137-140. Medline 11943209

Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K. J Biol Chem. 2002; 277: 39436-39442. Medline 12176993

Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. Umezu-Goto M, Kishi Y, Taira A, Hama K, Dohmae N, Takio K, Yamori T, Mills GB, Inoue K, Aoki J, Arai H. J Cell Biol. 2002; 158: 227-233. Medline 1211936

Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells. Yang SY, Lee J, Park CG, Kim S, Hong S, Chung HC, Min SK, Han JW, Lee HW, Lee HY. Clin Exp Metastasis. 2002; 19: 603-608. Medline 12498389

Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Clair T, Aoki J, Koh E, Bandle RW, Nam SW, Ptaszynska MM, Mills GB, Schiffmann E, Liotta LA, Stracke ML. Cancer Res. 2003; 62: 5446-5453. Medline 14500380

Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity. Ferry G, Tellier E, Try A, Gres S, Naime I, Simon MF, Rodriguez M, Boucher J, Tack I, Gesta S, Chomarat P, Dieu M, Raes M, Galizzi JP, Valet P, Boutin JA, Saulnier-Blache JS. J Biol Chem. 2003; 278: 18162-18169. Medline 12642576

Phosphodiesterase-Ialpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination. Fox MA, Colello RJ, Macklin WB, Fuss B. Mol Cell Neurosci. 2003; 23: 507-519. Medline 12837632

The hydrolysis of lysophospholipids and nucleotides by autotaxin (NPP2) involves a single catalytic site. Gijsbers R, Aoki J, Arai H, Bollen M. FEBS Lett. 2003; 538: 60-64. Medline 12633853

Site-directed mutations in the tumor-associated cytokine, autotaxin, eliminate nucleotide

Atlas Genet Cytogenet Oncol Haematol 2007; 3 392 phosphodiesterase, lysophospholipase D, and motogenic activities. Koh E, Clair T, Woodhouse EC, Schiffmann E, Liotta L, Stracke M. Cancer Res. 2003; 63: 2042-2045. Medline 12727817

Microarray analysis identifies Autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D activity, as a specific target of cell transformation by v-Jun. Black EJ, Clair T, Delrow J, Neiman P, Gillespie DA. Oncogene. 2004; 23: 2357-2366. Medline 14692828

Lipid phosphate phosphatases and related proteins: signaling functions in development, cell division, and cancer. Brindley DN. J Cell Biochem. 2004; 92: 900-912. [Review] Medline 1525891

Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1. Hama K, Aoki J, Fukaya M, Kishi Y, Sakai T, Suzuki R, Ohta H, Yamori T, Watanabe M, Chun J, Arai H. J Biol Chem. 2004; 279: 17634-17639. Medline 14744855

Expression, regulation and function of autotaxin in thyroid carcinomas. Kehlen A, Englert N, Seifert A, Klonisch T, Dralle H, Langner J, Hoang-Vu C. Int J Cancer. 2004; 109: 833-839. Medline 15027116

Induction of autotaxin by the Epstein-Barr virus promotes the growth and survival of Hodgkin lymphoma cells. Baumforth KR, Flavell JR, Reynolds GM, Davies G, Pettit TR, Wei W, Morgan S, Stankovic T, Kishi Y, Arai H, Nowakova M, Pratt G, Aoki J, Wakelam MJ, Young LS, Murray PG. Blood. 2005; 106: 2138-2146. Medline 15933052

Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression. Boucher J, Quilliot D, Praderes JP, Simon MF, Gres S, Guigne C, Prevot D, Ferry G, Boutin JA, Carpene C, Valet P, Saulnier-Blache JS. Diabetologia. 2005; 48: 569-577. Medline 15700135

Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells. Chen M, O'Connor KL. Oncogene. 2005; 24: 5125-5130. Medline 15897878

Footer: a quantitative comparative genomics method for efficient recognition of cis-regulatory elements.TER: a web tool for finding mammalian DNA regulatory regions using phylogenetic footprinting. Corcoran DL, Feingold E, Dominick J, Wright M, Harnaha J, Trucco M, Giannoukakis N, Benos PV. Genome Res. 2005; 15: 840-847. Medline 15930494

Atlas Genet Cytogenet Oncol Haematol 2007; 3 393

Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate. van Meeteren LA, Ruurs P, Christodoulou E, Goding JW, Takakusa H, Kikuchi K, Perrakis A, Nagano T, Moolenaar WH. J Biol Chem. 2005; 208: 21155-21161. Medline 15769751

The N-terminal hydrophobic sequence of autotaxin (ENPP2) functions as a signal peptide. Koike S, Keino-Masu K, Ohto T, Masu M. Genes Cells. 2006; 11: 133-142. Medline 16436050

Autotaxin stimulates urokinase-type plasminogen activator expression through phosphoinositide 3-kinase-Akt-necrosis factor kappa B signaling cascade in human melanoma cells. Lee J, Duk Jung I, Gyo Park C, Han JW, Young Lee H. Melanoma Res. 2006; 16: 445-452. Medline 17013094

Identification of large-scale molecular changes of Autotaxin (ENPP2) knock-down by small interfering RNA in breast cancer cells. Noh JH, Ryu SY, Eun JW, Song J, Ahn YM, Kim SY, Lee SH, Park WS, Yoo NJ, Lee JY, Lee SN, Nam SW. Mol Cel Biochem. 2006; 288: 91-106. Medline 16601922

The candidate tumor suppressor CST6 alters the gene expression profile of human breast carcinoma cells: down-regulation of the potent mitogenic, motogenic, and angiogenic factor autotaxin. Song J, Jie C, Polk P, Shridhar R, Clair T, Zhang J, Yin L, Keppler D. Biochem Biophys Res Commun. 2006; 340: 175-182. Medline 16356477

Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. Tanaka M, Okudaira S, Kishi Y, Ohkawa R, Iseki S, Ota M, Noji S, Yatomi Y, Aoki J, Arai H. J Biol Chem. 2006; 281: 25822-25830. Medline 16829511

Cyclic phosphatidic acid is produced by autotaxin in blood. Tsuda S, Okudaira S, Moriya-Ito K, Shimamoto C, Tanaka M, Aoki J, Arai H, Murakami-Murofushi K, Kobayashi T. J Biol Chem. 2006; 281: 26081-26088. Medline 16837466

Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. van Meeteren LA, Ruurs P, Stortelers C, Bouwman P, van Rooijen MA, Pradere JP, Pettit TR, Wakelam MJ, Saulnier-Blache JS, Mummery CL, Moolenaar WH, Jonkers J. Mol Cell Biol. 2006; 26: 501-522. Medline 16782887

Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N- glycosylation and signal peptidase. Pradere JP, Tarnus E, Gres S, Valet P, Saulnier-Blache JS.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 394 Biochim Biophys Acta. 2007; 1771: 93-102. Medline 17208043

Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma. Savaskan NE, Rocha L, Kotter MR, Baer A, Lubec G, van Meeteren LA, Kishi Y, Aoki J, Moolenaar WH, Nitsch R, Brauer AU. Cell Mol Life Sci. 2007; 64: 230-243. Medline 17192809

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Mary L. Stracke, Timothy Clair Citation This paper should be referenced as such : Stracke ML, Clair T . ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/ENPP2ID40455ch8q24.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 395 Atlas of Genetics and Cytogenetics in Oncology and Haematology

BRD4 (bromodomain containing 4) Identity Other names HUNK1 MCAP Hugo BRD4 Location 19p13 DNA/RNA Description The gene consists of 20 exons that span approximately 43 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon and stop codon are located to exon 2 and exon 20, respectively. Transcription Two isoforms of BRD4 have been reported. The "BRD4 long isoform" corresponds to the ordinary full length transcript while the "BRD4 short isoform" corresponds to an alternative splicing variant lacking exons 12-20. The "BRD4 long variant" encodes a 6.0 kb transcript and the "BRD4 short variant" encodes a 4.4 kb transcript. Protein Description BRD4 belongs to the BET subgroup of the bromodomain superfamily and contains 2 bromodomains and a conserved ET-domain. The open reading frame encodes a 1362 amino acid protein with a molecular weight of 200 kDa. Expression Northen blot analysis has shown an ubiquitous normal expression of both BRD4 isoforms. Localisation Nuclear. Function A striking feature of BRD4 is its association with euchromatic regions of mitotic chromosomes. By this association, the protein exerts its function as regulator of cell cycle progression from G2 to M but also in the G1 to S transition. It has also been suggested that the association of BRD4 to chromatin is important for the transmission of a transcriptional memory during cell division. Implicated in Entity Carcinoma with t(15;19)(q14;p13) translocation. Prognosis Carcinoma with t(15;19) translocation is invariably fatal with a rapid clinical course when located to the midline thoracic, head and neck structures. One tumor, displaying the cytogenetic and molecular cytogenetic features of carcinoma with t(15;19) translocation, but located to the iliac bone, has been reported as successfully cured. Cytogenetics t(15;19)(q14;p13) [reported breakpoints: t(15;19)(q11-15;p13)]. Hybrid/Mutated The t(15;19)(q14;p13) results in a BRD4-NUT chimeric gene where exon 10 of BRD4 Gene is fused to exon 2 of NUT. Abnormal The BRD4-NUT fusion protein is composed of the N-terminal of BRD4 (amino acids 1- Protein 720 out of 1372) and almost the entire protein sequence of NUT (amino acids 6- 1127). The N-terminal of BRD4 includes bromodomains 1 and 2 and other, less well characterized functional domains. Oncogenesis It has been suggested that the oncogenic effect of the NUT-BRD4 fusion is caused not only by the abnormal regulation of NUT by BRD4 promoter elements but also by the consequent ectopic expression of NUT in non-germinal tissues. Breakpoints Note The vast majority of reported 19p breakpoints were assigned to band 19p13, the

Atlas Genet Cytogenet Oncol Haematol 2007; 3 396 exception being the cytogenetic interpretation of a 19q13 breakpoint reported once. The reported breakpoints on chromosome 15 have varied (15q11-q15). External links Nomenclature Hugo BRD4 GDB BRD4 Entrez_Gene BRD4 23476 bromodomain containing 4 Cards Atlas BRD4ID837ch19p13 GeneCards BRD4 Ensembl BRD4 Genatlas BRD4 GeneLynx BRD4 eGenome BRD4 euGene 23476 Genomic and cartography GoldenPath BRD4 - 19p13 chr19:15218849-15252262 - 19p13.1 (hg18-Mar_2006) Ensembl BRD4 - 19p13.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene BRD4 Gene and transcription Genbank AF386649 [ ENTREZ ] Genbank BC000156 [ ENTREZ ] Genbank BC008354 [ ENTREZ ] Genbank BC030158 [ ENTREZ ] Genbank BC035266 [ ENTREZ ] RefSeq NM_014299 [ SRS ] NM_014299 [ ENTREZ ] RefSeq NM_058243 [ SRS ] NM_058243 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011295 [ SRS ] NT_011295 [ ENTREZ ] RefSeq NW_927195 [ SRS ] NW_927195 [ ENTREZ ] AceView BRD4 AceView - NCBI Unigene Hs.187763 [ SRS ] Hs.187763 [ NCBI ] HS187763 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O60885 [ SRS] O60885 [ EXPASY ] O60885 [ INTERPRO ] Prosite PS00633 BROMODOMAIN_1 [ SRS ] PS00633 BROMODOMAIN_1 [ Expasy ] Prosite PS50014 BROMODOMAIN_2 [ SRS ] PS50014 BROMODOMAIN_2 [ Expasy ] Interpro IPR001487 Bromodomain [ SRS ] IPR001487 Bromodomain [ EBI ] CluSTr O60885 PF00439 Bromodomain [ SRS ] PF00439 Bromodomain [ Sanger ] pfam00439 [ Pfam NCBI-CDD ] Smart SM00297 BROMO [EMBL]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 397 Blocks O60885 HPRD O60885 Protein Interaction databases DIP O60885 IntAct O60885 Polymorphism : SNP, mutations, diseases OMIM 608749 [ map ] GENECLINICS 608749 SNP BRD4 [dbSNP-NCBI] SNP NM_014299 [SNP-NCI] SNP NM_058243 [SNP-NCI] SNP BRD4 [GeneSNPs - Utah] BRD4] [HGBASE - SRS] HAPMAP BRD4 [HAPMAP] COSMIC BRD4 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family BRD4 [UCSC Family Browser] Browser SOURCE NM_014299 SOURCE NM_058243 SMD Hs.187763 SAGE Hs.187763 GO nucleus [Amigo] nucleus PubGene BRD4 Other databases Probes Probe BRD4 Related clones (RZPD - Berlin) PubMed PubMed 18 Pubmed reference(s) in LocusLink Bibliography Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19). Kees UR, Mulcahy MT, Willoughby MLN. Am J Pediatr Hematol Oncol. 1991; 13: 459-464. Medline 1785673

A bromodomain protein MCAP, associates with mitotic chromosomes and affects G2-to-M transition. Dey A, Ellenberg J, Farina A, Coleman AE, Maruyama T, Sciortino S, Lippincott-Schwartz J, Ozato K. Mol Cell Biol. 2000; 20: 6537-6549. Medline 10938129

You bet-cha: a novel family of transcriptional regulators. Florence B, Faller DV. Front Biosci. 2001; 6: D1008-1018. Medline 11487468

BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR,

Atlas Genet Cytogenet Oncol Haematol 2007; 3 398 Fletcher JA. Am J Pathol. 2001; 159: 1987-1992. Medline 11733348

A mammalian bromodomein protein, Brd4, interacts with replication factor C and inhibits progression to S phase. Maruyama T, Farina A, dey A, Cheong JH, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K. Mol Cell Biol. 2002; 22: 6509-6520. Medline 12192049

The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitois. Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. Proc Natl Acad Sci USA. 2003; 100: 8758-8763. Medline 12840145

BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. Cancer Res. 2003;63: 304-307. Medline 12543779

Midline carcinoma of children and young adults with NUT rearrangement. French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, Nose V, Vargas SO, Moschovi M, Tzortzatou-Stathopoulo F, Miyoshi I, Perez-Atayde AR, Aster JC, Fletcher JA. J Clin Oncol. 2004; 22: 4135-4139. Medline 15483023

Carcinoma with t(15;19) translocation. Marx A, French CA, Fletcher JA. In: World Health Organization classification of tumours. Pathology and genetics of tumours of the lung, thymus, pleura and heart. Travis WD, Brambilla E, Muller-Hermelink K, Harris CC, editors. Oxford University Press 2004. pp. 185-186.

Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. You J, Croyle JL, Nishimura A, Ozato K, Howley P. Cell. 2004; 117: 349-360. Medline 15109495

Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy. Engleson J, Soller M, Panagopoulos I, Dahlén A, Dictor M, Jerkeman M. BMC Cancer. 2006; 6: 69. Medline 16542442

Successful treatment of a child with t(15;19)-positive tumor. Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA. Pediatr Blood Cancer. 2006. Medline 16435379

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

Atlas Genet Cytogenet Oncol Haematol 2007; 3 399 BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Anna Collin Citation This paper should be referenced as such : Collin A . BRD4 (bromodomain containing 4). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/BRD4ID837ch19p13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 400 Atlas of Genetics and Cytogenetics in Oncology and Haematology

BCL6 (B-Cell Lymphoma 6) Identity Other names LAZ3 ( Lymphoma Associated Zinc finger on chromosome 3) ZNF51 (Zinc Finger Protein 51) Hugo BCL6 Location 3q27 Local_order gene orientation: telomere - 5' LAZ3 3' - centromere

BCL6 (3q27) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA Description The gene is encoded by 11 exons that are located on Chromosome 3q27 and is 24.3 kb. The 5¹ portion encodes for the BTB/POZ domain (broad-complex/tramtrack/bric-a- brac/pox virus/zinc finger), while the 3¹ end encodes for 6 DNA binding zinc fingers. The first ATG occurs in exon 3. Transcription 3.8 kb mRNA Protein Description The protein product is 706 amino acids with an estimated molecular weight of 78.8 kDa. Expression Normally expressed in germinal center B and T cells,other lymphoid tissues, in skeletal muscle cells and in keratinocytes. Localisation Nuclear paraspeckles/dots Function The protein can bind to sequence specific DNA and repress its transcription in addition to recruiting other protein repressors. The DNA binding is mediated through the consensus sequence: TTCCT(A/C)GAA while the protein-protein interactions are mediated through the BTB/POZ domain and it has been shown to interact with other zinc finger proteins and corepressors (including Deacetylase 1 (HDAC1)and Silencing Mediator of Retinoid and Thryoid Receptor 1 (SMRT1)). The carboxy terminus, on the other hand, is responsible for sequence specific DNA binding through its 6 zinc fingers. Homology BTB/POZ - Zinc Finger proteins (PLZF, HIC1, KUP, BAZF, ttk (drosophila), BrC (drosophila)...).

Atlas Genet Cytogenet Oncol Haematol 2007; 3 401 Implicated in Entity 3q27 rearrangements /NHL (non Hodgkin lymphomas) Disease B cell non-Hodgkin Lymphoma (B-NHL) carry the greatest number of translocations involving the BCL6 gene locus. Translocations are most commonly detected within 15-40% of Diffuse Large B-Cell Lymphomas (DLBCL), 6-15% of Follicular Lymphomas (FL), and 50% of nodular lymphocyte predominant Hodgkin Lymphomas. Prognosis Generally considered to be a better prognosis if there is increased expression of BCL6. The mechanism by which its expression is increased does not seem to matter (ie different translocation partners increasing its expression results in the same prognosis). Cytogenetics 3q27 rearrangements/aberrations are diverse and include: translocations, micro- deletions, point mutations and hypermutation. Approximately 50% of 3q27 translocations involves Ig genes at 14q32 (IgH), 2p12 (IgK) and 22q12 (IgL) (e.g. t(3;14)(q27;q32). Less than half (~40%) include a variety of other chromosomal regions (1q21, 2q21, 4p11, 5q31, 6p21, 7p12, 8q24, 9p13, 11q13, 11q23, 12q11, 13q14-21, 14q11, 15q21; 16p11...). In addition, there are frequent bi-allelic alterations (translocation and deletion or mutation on the non-translocated allele). Hybrid/Mutated Hybrid gene and transcripts are formed following promoter substitution between BCL6 Gene and its different partners. Chimeric transcripts are generally detected containing the 5' part of the gene partner fused to the normal BCL6 exon 2 splice acceptor site. In some cases reciprocal chimeric transcripts driven by the 5' regulatory region of BCL6 fused to the partner gene coding region, have been characterised. t(2;3)(p12;q27) the gene in 2p12 is IGK t(3;3)(q25;q27) the gene in 3q25 is MBNL1 t(3;3)(q27;q27) the gene in 3q27 is ST6GAL1 t(3;3)(q27;q27) the gene in 3q27 is EIF4A2 t(3;3)(q27;q29) the gene in 3q29 is TFRC t(3;4)(q27;p13) the gene in 4p13 is RHOH t(3;6)(q27;p22) the gene in 6p22 is HIST1H4I t(3;6)(q27;p21) the gene in 6p21 is PIM1 t(3;6)(q27;p21) the gene in 6p21 is SFRS3 t(3;6)(q27;p21) the gene in 6p21 isHistone H4 t(3;6)(q27;p12) the gene in 6p12 is HSP90AB1 t(3;6)(q27;q15) the gene in 6q15 is SNHG5 t(3;7)(q27;p12) the gene in 7p12 is IKZF1 t(3;8)(q27;q24.1) the gene in 8q24.1 is MYC t(3;9)(q27;p11) the gene in 9p11 is GRHPR t(3;11)(q27;q23) the gene in 11q23 is POU2AF1 t(3;12)(q27;p13) the gene in 12p13 is GAPDH t(3;12)(q27;q12) the gene in 12q12 is LRMP t(3;12)(q27;q23) the gene in 12q23 is NACA t(3;13)(q27;q14) the gene in 13q14 is LCP1 t(3;14)(q27;q32) the gene in 14q32 is IGH t(3;14)(q27;q32) the gene in 14q32 is HSP90AA1 t(3;16)(q27;p13) the gene in 16p13 is CIITA t(3;16)(q27;p11) the gene in 16p11 is IL21R t(3;19)(q27;q13) the gene in 19q13 is NAPA t(3;22)(q27;q11) the gene in 22q11 is IGL Abnormal no fusion protein Protein Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2007; 3 402

Note Clustered in a 3,3kb EcoRI fragment (MTC) includind exon 1A and intron 1. External links Nomenclature Hugo BCL6 GDB BCL6 Entrez_Gene BCL6 604 B-cell CLL/lymphoma 6 (zinc finger protein 51) Cards Atlas BCL6ID20 GeneCards BCL6 Ensembl BCL6 Genatlas BCL6 GeneLynx BCL6 eGenome BCL6 euGene 604 Genomic and cartography GoldenPath BCL6 - 3q27 chr3:188921859-188946169 - 3q27 (hg18-Mar_2006) Ensembl BCL6 - 3q27 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene BCL6 Gene and transcription Genbank AI624861 [ ENTREZ ] Genbank BC142705 [ ENTREZ ] Genbank BX649185 [ ENTREZ ] Genbank S67779 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 403 Genbank U00115 [ ENTREZ ] RefSeq NM_001706 [ SRS ] NM_001706 [ ENTREZ ] RefSeq NM_138931 [ SRS ] NM_138931 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_005612 [ SRS ] NT_005612 [ ENTREZ ] RefSeq NW_921807 [ SRS ] NW_921807 [ ENTREZ ] AceView BCL6 AceView - NCBI Unigene Hs.478588 [ SRS ] Hs.478588 [ NCBI ] HS478588 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P41182 [ SRS] P41182 [ EXPASY ] P41182 [ INTERPRO ] Prosite PS50097 BTB [ SRS ] PS50097 BTB [ Expasy ] PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 ZINC_FINGER_C2H2_1 [ Prosite Expasy ] PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 ZINC_FINGER_C2H2_2 [ Prosite Expasy ] Interpro IPR000210 BTB [ SRS ] IPR000210 BTB [ EBI ] Interpro IPR013069 BTB_POZ [ SRS ] IPR013069 BTB_POZ [ EBI ] Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] CluSTr P41182 Pfam PF00651 BTB [ SRS ] PF00651 BTB [ Sanger ] pfam00651 [ NCBI-CDD ] Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ] Smart SM00225 BTB [EMBL] Smart SM00355 ZnF_C2H2 [EMBL] Blocks P41182 PDB 1R28 [ SRS ] 1R28 [ PdbSum ], 1R28 [ IMB ] 1R28 [ RSDB ] PDB 1R29 [ SRS ] 1R29 [ PdbSum ], 1R29 [ IMB ] 1R29 [ RSDB ] PDB 1R2B [ SRS ] 1R2B [ PdbSum ], 1R2B [ IMB ] 1R2B [ RSDB ] HPRD P41182 Protein Interaction databases DIP P41182 IntAct P41182 Polymorphism : SNP, mutations, diseases OMIM 109565 [ map ] GENECLINICS 109565 SNP BCL6 [dbSNP-NCBI] SNP NM_001706 [SNP-NCI] SNP NM_138931 [SNP-NCI] SNP BCL6 [GeneSNPs - Utah] BCL6] [HGBASE - SRS] HAPMAP BCL6 [HAPMAP] COSMIC BCL6 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family BCL6 [UCSC Family Browser] Browser

Atlas Genet Cytogenet Oncol Haematol 2007; 3 404 SOURCE NM_001706 SOURCE NM_138931 SMD Hs.478588 SAGE Hs.478588 protein import into nucleus, translocation [Amigo] protein import into nucleus, GO translocation negative regulation of transcription from RNA polymerase II promoter GO [Amigo] negative regulation of transcription from RNA polymerase II promoter GO cell morphogenesis [Amigo] cell morphogenesis negative regulation of cell-matrix adhesion [Amigo] negative regulation of cell-matrix GO adhesion regulation of germinal center formation [Amigo] regulation of germinal center GO formation negative regulation of T-helper 2 type immune response [Amigo] negative regulation GO of T-helper 2 type immune response GO negative regulation of B cell apoptosis [Amigo] negative regulation of B cell apoptosis GO DNA binding [Amigo] DNA binding GO chromatin binding [Amigo] chromatin binding GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO replication fork [Amigo] replication fork GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO response to DNA damage stimulus [Amigo] response to DNA damage stimulus GO Rho protein signal transduction [Amigo] Rho protein signal transduction GO spermatogenesis [Amigo] spermatogenesis GO protein localization [Amigo] protein localization GO zinc ion binding [Amigo] zinc ion binding GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation GO transcriptional repressor activity [Amigo] transcriptional repressor activity GO transcriptional repressor activity [Amigo] transcriptional repressor activity actin cytoskeleton organization and biogenesis [Amigo] actin cytoskeleton GO organization and biogenesis GO B cell differentiation [Amigo] B cell differentiation GO negative regulation of cell growth [Amigo] negative regulation of cell growth positive regulation of B cell proliferation [Amigo] positive regulation of B cell GO proliferation GO regulation of Rho GTPase activity [Amigo] regulation of Rho GTPase activity negative regulation of mast cell cytokine production [Amigo] negative regulation of GO mast cell cytokine production negative regulation of Rho protein signal transduction [Amigo] negative regulation of GO Rho protein signal transduction GO T-helper 2 type immune response [Amigo] T-helper 2 type immune response

Atlas Genet Cytogenet Oncol Haematol 2007; 3 405 GO positive regulation of apoptosis [Amigo] positive regulation of apoptosis regulation of memory T cell differentiation [Amigo] regulation of memory T cell GO differentiation GO sequence-specific DNA binding [Amigo] sequence-specific DNA binding negative regulation of cell differentiation [Amigo] negative regulation of cell GO differentiation negative regulation of T-helper 2 cell differentiation [Amigo] negative regulation of T- GO helper 2 cell differentiation negative regulation of S phase of mitotic cell cycle [Amigo] negative regulation of S GO phase of mitotic cell cycle GO metal ion binding [Amigo] metal ion binding negative regulation of isotype switching to IgE isotypes [Amigo] negative regulation of GO isotype switching to IgE isotypes GO erythrocyte development [Amigo] erythrocyte development GO regulation of inflammatory response [Amigo] regulation of inflammatory response GO regulation of immune response [Amigo] regulation of immune response GO positive regulation of cell motility [Amigo] positive regulation of cell motility PubGene BCL6 Other databases Probes Probe BCL6 Related clones (RZPD - Berlin) PubMed PubMed 93 Pubmed reference(s) in LocusLink Bibliography LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G, Bastard C Nat Genet. 1993; 5(1): 66-70 Medline 8220427

Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, Chaganti RS, Dalla-Favera R Science 1993; 262(5134): 747-750 Medline 8235596

Gene involved in the 3q27 translocation associated with B-cell lymphoma, BCL5, encodes a Kruppel-like zinc-finger protein. Miki T, Kawamata N, Hirosawa S, Aoki N Blood. 1994; 83(1): 26-32 Medline 8274740

High BCL6 expression predicts better prognosis, independent of BCL6 translocation status, translocation partner, or BCL6 deregulating mutations, in gastric lymphoma Chen YW, Hu XT, Liang AC, Au WY, So CC, Wong ML, Shen L, Tao Q, Chu KM, Kwong YL, Liang RH, Srivastava G. Blood. 2006; 108 (7): 2373-2383. Medline 16772602

Intrachromosomal rearrangement of chromosome 3q27: an under recognized mechanism of BCL6 translocation in B-cell non-Hodgkin lymphoma.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 406 Keller CE, Nandula S, Vakiani E, Alobeid B, Murty VV, Bhagat G. Hum Pathol. 2006; 37(8): 1093-1099. Medline 16867873

Prognostic impact of chromosomal alteration of 3q27 on nodal B-cell lymphoma: Correlation with histology, immunophenotype, karyotype, and clinical outcome in 329 consecutive patients. Niitsu N, Okamoto M, Nakamura N, Nakamine H, Aoki S, Hirano M, Miura I. Leuk Res. 2006; Medline 17197022

Pathogenetic and clinical implications of non-immunoglobulin ; BCL6 translocations in B-cell non-Hodgkin's lymphoma. Ohno H. J Clin Exp Hematop. 2006; 46(2): 43-53. Review. Medline 17142954

A novel t(2;3)(p11;q27) in a case of follicular lymphoma. Tapinassi C, Micucci C, Lahortiga I, Malazzi O, Gasparini P, Gorosquieta A, Odero MD, Belloni E. Cancer Genet Cytogenet. 2007; 172(1): 70-73. Medline 17175383

A novel t(3;8)(q27;q24.1) simultaneously involving both the BCL6 and MYC genes in a diffuse large B-cell lymphoma. Wang HY, Bossler AD, Schaffer A, Tomczak E, DiPatri D, Frank DM, Nowell PC, Bagg A. Cancer Genet Cytogenet. 2007; 172(1): 45-53. Medline 17175379

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 09-1998 Jean-Pierre Kerkaert Updated 02-2007 Stevan Knezevich Citation This paper should be referenced as such : Kerkaert JP . BCL6 (B-Cell Lymphoma 6). Atlas Genet Cytogenet Oncol Haematol. September 1998 . URL : http://AtlasGeneticsOncology.org/Genes/BCL6ID20.html Knezevich S . BCL6 (B-Cell Lymphoma 6). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/BCL6ID20.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 407 Atlas of Genetics and Cytogenetics in Oncology and Haematology

BARD1 (BRCA1 associated RING domain 1) Identity Other names BRCA1-associated RING domain protein 1 Hugo BARD1 Location 2q35 Local_order Antiparallel DNA/RNA

BARD1 structure is presented with RING finger (green) ankyrin repeats (ANK, blue) and BRCT domains (red). Positions of introns (in) are indicated. Structures of splice variants are shown for BARD1beta from the rat (Feki et al., 2004), BARD1delta (Feki et al., 2005; Tsuzuki et al., 2006).

Description The gene spans 81 kb, composed of 11 exons. Alternatively spliced isoforms are identified. Insert known isoforms: BARD1beta (rat testis) BARD1delta (rat ovarian cancer cells) BARD1delta (HeLa) BARD1delta (rat ovarian cancer cells) Transcription Transcription start is 100 bp upstream of first ATG of the BARD1 ORF. There a two 3¹ends reported and possibly two alternative polyadenylation sites. BARD1 is expressed in most proliferative tissues. Highest expression in testis and spleen. No expression the central nervous system. Pseudogene No pseudogenes reported. Protein

Mouse and human BARD1 protein sequences are shown schematically. RING finger domains (gren), Ankyrin repeats (ANK, blue), BRCT domains (red), nulear localization signals (light blue). Homology between human and mouse BARD1 is indicated in perentage of identical amino acids for structural regions. Description Human BARD1 777 amino acids ; Structural motifs: RING, 5 Ankyrin repeats, 2 BRCT

Atlas Genet Cytogenet Oncol Haematol 2007; 3 408 domains Expression In the mouse BARD1 is expressed in most proliferative tissues. Highest expression in testis and spleen, no expression in nervous system. During mouse development BARD1 is expressed in early embryogenesis and declines after day 9. Localisation During S-phase BARD1 localizes to nuclear dots. Partially, BARD1 is also localized to the cytoplasm in response to stress. Function BARD1 functions as heterodimer with BRCA1 as . Several targets of the BARD1-BRCA1 have been identified and suggest its implication in DNA repair, polyadenylation, cell cycle control, and mitosis. BARD1 acts as inducer of apoptosis, independently of BRCA1, by binding to p53, and by binding to the stress response kinase DNA-PK, facilitating p53 phosphorylation and stabilization. Thus BARD1 acts as signaling molecule from genotoxic stress towards p53-dependent apoptosis. Homology BARD1 is homologous to BRCA1, regarding the N-terminal RING finger and the C- terminal BRCT domains. Weak homology between BARD1 and BRCA1 can be found throughout exon 1 to exon 4. and from exon 7 through exon 11, with conserved intron- exon junctions. Mutations Note Several mutations of BARD1 have been identified in breast and ovarian cancers. Three mutations have been reported associated with inherited predisposition to breast and ovarian cancer.

BARD1 mutations associated with cancer. Small mutations are not unambiguously identified as cancer causing mutations, long arrows red labeled mutations are accepted as cancer associated. Blue indication maps germ line mutations. Q406R, might be cancer associated.

Germinal Germline mutations were reported for C557S and Q564H. Somatic Several somatic mutation were reported in addition to C557S and Q564H: Implicated in Entity Breast and/or ovarian cancer Note Upregulated expression of truncated BARD1 in epithelial cancers. Prognosis Upregulated BARD1 is correlated with poor prognosis in breast and ovarian cancer. Cytogenetics No determined Hybrid/Mutated Not determined Gene Abnormal No fusion proteins reported Protein

Entity Ovarian cancer Prognosis Upregulated BARD1 is correlated with poor prognosis in breast and ovarian cancer.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 409 Hybrid/Mutated No Gene Abnormal No fusion proteins reported Protein

Entity Lung cancer Prognosis Upregulated BARD1 is correlated with poor prognosis in breast and ovarian cancer. Hybrid/Mutated No Gene Abnormal No fusion proteins reported Protein External links Nomenclature Hugo BARD1 GDB BARD1 Entrez_Gene BARD1 580 BRCA1 associated RING domain 1 Cards Atlas BARD1ID756ch2q35 GeneCards BARD1 Ensembl BARD1 Genatlas BARD1 GeneLynx BARD1 eGenome BARD1 euGene 580 Genomic and cartography GoldenPath BARD1 - 2q35 chr2:215301522-215382611 - 2q34-q35 (hg18-Mar_2006) Ensembl BARD1 - 2q34-q35 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene BARD1 Gene and transcription Genbank AK223409 [ ENTREZ ] Genbank BC126426 [ ENTREZ ] Genbank BC126428 [ ENTREZ ] Genbank CR621362 [ ENTREZ ] Genbank U76638 [ ENTREZ ] RefSeq NM_000465 [ SRS ] NM_000465 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ] RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_005403 [ SRS ] NT_005403 [ ENTREZ ] RefSeq NW_921618 [ SRS ] NW_921618 [ ENTREZ ] AceView BARD1 AceView - NCBI Unigene Hs.591642 [ SRS ] Hs.591642 [ NCBI ] HS591642 [ spliceNest ] Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2007; 3 410 SwissProt Q53F80 [ SRS] Q53F80 [ EXPASY ] Q53F80 [ INTERPRO ] Prosite PS50297 ANK_REP_REGION [ SRS ] PS50297 ANK_REP_REGION [ Expasy ] Prosite PS50088 ANK_REPEAT [ SRS ] PS50088 ANK_REPEAT [ Expasy ] Prosite PS50172 BRCT [ SRS ] PS50172 BRCT [ Expasy ] Prosite PS00518 ZF_RING_1 [ SRS ] PS00518 ZF_RING_1 [ Expasy ] Prosite PS50089 ZF_RING_2 [ SRS ] PS50089 ZF_RING_2 [ Expasy ] Interpro IPR002110 ANK [ SRS ] IPR002110 ANK [ EBI ] Interpro IPR001357 BRCT [ SRS ] IPR001357 BRCT [ EBI ] Interpro IPR001841 Znf_RING [ SRS ] IPR001841 Znf_RING [ EBI ] CluSTr Q53F80 Pfam PF00023 Ank [ SRS ] PF00023 Ank [ Sanger ] pfam00023 [ NCBI-CDD ] Pfam PF00533 BRCT [ SRS ] PF00533 BRCT [ Sanger ] pfam00533 [ NCBI-CDD ] Smart SM00248 ANK [EMBL] Smart SM00292 BRCT [EMBL] Smart SM00184 RING [EMBL] Blocks Q53F80 HPRD Q53F80 Protein Interaction databases DIP Q53F80 IntAct Q53F80 Polymorphism : SNP, mutations, diseases OMIM 114480;601593 [ map ] GENECLINICS 114480;601593 SNP BARD1 [dbSNP-NCBI] SNP NM_000465 [SNP-NCI] SNP BARD1 [GeneSNPs - Utah] BARD1] [HGBASE - SRS] HAPMAP BARD1 [HAPMAP] COSMIC BARD1 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family BARD1 [UCSC Family Browser] Browser SOURCE NM_000465 SMD Hs.591642 SAGE Hs.591642 GO ubiquitin ligase complex [Amigo] ubiquitin ligase complex GO tissue homeostasis [Amigo] tissue homeostasis GO RNA binding [Amigo] RNA binding GO ubiquitin-protein ligase activity [Amigo] ubiquitin-protein ligase activity GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO response to DNA damage stimulus [Amigo] response to DNA damage stimulus

Atlas Genet Cytogenet Oncol Haematol 2007; 3 411 GO cell cycle arrest [Amigo] cell cycle arrest GO zinc ion binding [Amigo] zinc ion binding GO protein ubiquitination [Amigo] protein ubiquitination GO kinase binding [Amigo] kinase binding GO BRCA1-BARD1 complex [Amigo] BRCA1-BARD1 complex negative regulation of mRNA 3'-end processing [Amigo] negative regulation of mRNA GO 3'-end processing GO regulation of phosphorylation [Amigo] regulation of phosphorylation GO protein homodimerization activity [Amigo] protein homodimerization activity GO positive regulation of apoptosis [Amigo] positive regulation of apoptosis GO negative regulation of apoptosis [Amigo] negative regulation of apoptosis positive regulation of protein catabolic process [Amigo] positive regulation of protein GO catabolic process negative regulation of protein export from nucleus [Amigo] negative regulation of GO protein export from nucleus GO metal ion binding [Amigo] metal ion binding GO protein heterodimerization activity [Amigo] protein heterodimerization activity BIOCARTA BRCA1-dependent Ub-ligase activity [Genes] PubGene BARD1 Other databases Probes Probe BARD1 Related clones (RZPD - Berlin) PubMed PubMed 56 Pubmed reference(s) in LocusLink Bibliography Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL, Yang MC, Hwang LY, Bowcock AM, Baer R. Nat Genet. 1996; 14(4): 430-440. Medline 8944023

BRCA1 is a component of the RNA polymerase II holoenzyme. Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM, Parvin JD. Proc Natl Acad Sci U S A. 1997; 94(11): 5605-5610. Medline 9159119

Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, Livingston DM. Cell. 1997; 90(3): 425-435. Medline 9267023

Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein. Ayi TC, Tsan JT, Hwang LY, Bowcock AM, Baer R. Oncogene. 1998; 17(16): 2143-2148. Medline 9798686

Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in

Atlas Genet Cytogenet Oncol Haematol 2007; 3 412 mitotic and meiotic cells. Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R. Mol Cell. 1998; 2(3): 317-328. Medline 9774970

In vitro repression of Brca1-associated RING domain gene, Bard1, induces phenotypic changes in mammary epithelial cells. Irminger-Finger I, Soriano JV, Vaudan G, Montesano R, Sappino AP. J Cell Biol. 1998; 143(5): 1329-1339. Medline 9832560

Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Thai TH, Du F, Tsan JT, Jin Y, Phung A, Spillman MA, Massa HF, Muller CY, Ashfaq R, Mathis JM, Miller DS, Trask BJ, Baer R, Bowcock AM. Hum Mol Genet. 1998; 7(2): 195-202. Medline 9425226

The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co- regulators. Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, Scheidereit C, Leutz A. Oncogene. 1999; 18(22): 3316-3323. Medline 10362352

Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50. Kleiman FE, Manley JL. Science. 1999; 285(5433): 1576-1579. Medline 10477523

Identification of an apoptotic cleavage product of BARD1 as an autoantigen: a potential factor in the antitumoral response mediated by apoptotic bodies. Gautier F, Irminger-Finger I, Gregoire M, Meflah K, Harb J. Cancer Res. 2000; 60(24): 6895-6900. Medline 11156388

Structure of a BRCA1-BARD1 heterodimeric RING-RING complex. Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE. Nat Struct Biol. 2001; 8(10): 833-837. Medline 11573085

The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer- derived mutation. Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y, Ogata H, Ohta T. J Biol Chem. 2001; 276(18): 14537-14540. Medline 11278247

The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression. Kleiman FE, Manley JL. Cell. 2001; 104(5): 743-53. Medline 11257228

Identification of BARD1 as mediator between proapoptotic stress and p53-dependent

Atlas Genet Cytogenet Oncol Haematol 2007; 3 413 apoptosis. Irminger-Finger I, Leung WC, Li J, Dubois-Dauphin M, Harb J, Feki A, Jefford CE, Soriano JV, Jaconi M, Montesano R, Krause KH. Mol Cell. 2001; 8(6): 1255-1266. Medline 11779501

Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase. Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ. J Biol Chem. 2002; 277(24): 22085-22092. Medline 11927591

The BRCA1 and BARD1 association with the RNA polymerase II holoenzyme. Chiba N, Parvin JD. Cancer Res. 2002; 62(15): 4222-4228. Medline 12154023

BARD1 induces BRCA1 intranuclear foci formation by increasing RING-dependent BRCA1 nuclear import and inhibiting BRCA1 nuclear export. Fabbro M, Rodriguez JA, Baer R, Henderson BR. J Biol Chem. 2002; 277(24): 21315-21324. Medline 11925436

Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Ghimenti C, Sensi E, Presciuttini S, Brunetti IM, Conte P, Bevilacqua G, Caligo MA. Genes Chromosomes Cancer. 2002; 33(3): 235-242. Medline 11807980

BRCA1-dependent and independent functions of BARD1. Irminger-Finger I, Leung WC. Int J Biochem Cell Biol. 2002; 34(6): 582-587. Medline 11943588

Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. Mallery DL, Vandenberg CJ, Hiom K. EMBO J. 2002; 21(24): 6755-6762. Medline 12485996

Identification of residues required for the interaction of BARD1 with BRCA1. Morris JR, Keep NH, Solomon E. J Biol Chem. 2002; 277(11): 9382-9386. Medline 11773071

E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA, Dynlacht BD. Genes Dev. 2002; 16(2): 245-256. Medline 11799067

Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway. Spahn L, Petermann R, Siligan C, Schmid JA, Aryee DN, Kovar H. Cancer Res. 2002; 62(16): 4583-4587. Medline 12183411

Atlas Genet Cytogenet Oncol Haematol 2007; 3 414 Mutational analysis of BARD1 in familial breast cancer patients in Japan. Ishitobi M, Miyoshi Y, Hasegawa S, Egawa C, Tamaki Y, Monden M, Noguchi S. Cancer Lett. 2003; 200(1): 1-7. Medline 14550946

Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. McCarthy EE, Celebi JT, Baer R, Ludwig T. Mol Cell Biol. 2003; 23(14): 5056-5063. Medline 12832489

BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks. Westermark UK, Reyngold M, Olshen AB, Baer R, Jasin M, Moynahan ME. Mol Cell Biol. 2003; 23(21): 7926-7936. Medline 14560035

Ubiquitination and proteasomal degradation of the BRCA1 tumor suppressor is regulated during cell cycle progression. Choudhury AD, Xu H, Baer R. J Biol Chem. 2004; 279(32): 33909-33918. Medline 15166217

BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. Fabbro M, Savage K, Hobson K, Deans AJ, Powell SN, McArthur GA, Khanna KK. J Biol Chem. 2004; 279(30): 31251-31258. Medline 15159397

BARD1 regulates BRCA1 apoptotic function by a mechanism involving nuclear retention. Fabbro M, Schuechner S, Au WW, Henderson BR. Exp Cell Res. 2004; 298(2): 661-673. Medline 15265711

BARD1 expression during spermatogenesis is associated with apoptosis and hormonally regulated. Feki A, Jefford CE, Durand P, Harb J, Lucas H, Krause KH, Irminger-Finger I. Biol Reprod. 2004; 71(5): 1614-1624. Medline 15240424

Nuclear-cytoplasmic translocation of BARD1 is linked to its apoptotic activity. Jefford CE, Feki A, Harb J, Krause KH, Irminger-Finger I. Oncogene. 2004; 23(20): 3509-3520. Medline 15077185

Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer. Karppinen SM, Heikkinen K, Rapakko K, Winqvist R. J Med Genet. 2004; 41(9): e114. Medline 15342711

BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Morris JR, Solomon E. Hum Mol Genet. 2004; 13(8): 807-817.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 415 Medline 14976165

Nuclear-cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1. Rodriguez JA, Schuchner S, Au WW, Fabbro M, Henderson BR. Oncogene. 2004; 23(10): 1809-1820. Medline 14647430

Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase. Sato K, Hayami R, Wu W, Nishikawa T, Nishikawa H, Okuda Y, Ogata H, Fukuda M, Ohta T. J Biol Chem. 2004; 279(30): 30919-30922. Medline 15184379

BRCA1-dependent ubiquitination of gamma- regulates centrosome number. Starita LM, Machida Y, Sankaran S, Elias JE, Griffin K, Schlegel BP, Gygi SP, Parvin JD. Mol Cell Biol. 2004; 24(19): 8457-8466. Medline 15367667

Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Stark JM, Pierce AJ, Oh J, Pastink A, Jasin M. Mol Cell Biol. 2004; 24(21): 9305-9316. Medline 15485900

Hyperphosphorylation of the BARD1 tumor suppressor in mitotic cells. Choudhury AD, Xu H, Modi AP, Zhang W, Ludwig T, Baer R. J Biol Chem. 2005; 280(26): 24669-24679. Medline 15855157

BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. Feki A, Jefford CE, Berardi P, Wu JY, Cartier L, Krause KH, Irminger-Finger I. Oncogene. 2005; 24(23): 3726-3736. Medline 15782130

Role of nucleophosmin in embryonic development and tumorigenesis. Grisendi S, Bernardi R, Rossi M, Cheng K, Khandker L, Manova K, Pandolfi PP. Nature. 2005; 437(7055): 147-153. Medline 16007073

Down-regulation of BRCA1-BARD1 ubiquitin ligase by CDK2. Hayami R, Sato K, Wu W, Nishikawa T, Hiroi J, Ohtani-Kaneko R, Fukuda M, Ohta T. Cancer Res. 2005; 65(1): 6-10. Medline 15665273

BRCA1/BARD1 inhibition of mRNA 3' processing involves targeted degradation of RNA polymerase II. Kleiman FE, Wu-Baer F, Fonseca D, Kaneko S, Baer R, Manley JL. Genes Dev. 2005; 19(10): 1227-1237. Medline 15905410

Nuclear targeting and cell cycle regulatory function of human BARD1. Schuchner S, Tembe V, Rodriguez JA, Henderson BR. J Biol Chem. 2005; 280(10): 8855-8861. Medline 15632137

Atlas Genet Cytogenet Oncol Haematol 2007; 3 416

BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II. Starita LM, Horwitz AA, Keogh MC, Ishioka C, Parvin JD, Chiba N. J Biol Chem. 2005; 280(26): 24498-24505. Medline 15886201

BARD1 content correlates with increased DNA fragmentation associated with muscle wasting in tumour-bearing rats. Irminger-Finger I, Busquets S, Calabrio F, Lopez-Soriano FJ, Argiles JM. Oncol Rep. 2006; 15(6): 1425-1458. Medline 16685375

Is there more to BARD1 than BRCA1? Irminger-Finger I, Jefford CE. Nat Rev Cancer. 2006; 6(5): 382-391. Medline 16633366

The BRCA1/BARD1 heterodimer modulates -dependent mitotic spindle assembly. Joukov V, Groen AC, Prokhorova T, Gerson R, White E, Rodriguez A, Walter JC, Livingston DM. Cell. 2006; 127(3): 539-552. Medline 17081976

Nordic collaborative study of the BARD1 Cys557Ser allele in 3956 patients with cancer: enrichment in familial BRCA1/BRCA2 mutation-negative breast cancer but not in other malignancies. Karppinen SM, Barkardottir RB, Backenhorn K, Sydenham T, Syrjakoski K, Schleutker J, Ikonen T, Pylkas K, Rapakko K, Erkko H, Johannesdottir G, Gerdes AM, Thomassen M, Agnarsson BA, Grip M, Kallioniemi A, Kere J, Aaltonen LA, Arason A, Moller P, Kruse TA, Borg A, Winqvist R. J Med Genet. 2006; 43(11): 856-862. Medline 16825437

The BARD1 Cys557Ser variant and breast cancer risk in Iceland. Stacey SN, Sulem P, Johannsson OT, Helgason A, Gudmundsson J, Kostic JP, Kristjansson K, Jonsdottir T, Sigurdsson H, Hrafnkelsson J, Johannsson J, Sveinsson T, Myrdal G, Grimsson HN, Bergthorsson JT, Amundadottir LT, Gulcher JR, Thorsteinsdottir U, Kong A, Stefansson K. PLoS Med. 2006; 3(7): e217. Medline 16768547

A truncated splice variant of human BARD1 that lacks the RING finger and ankyrin repeats. Tsuzuki M, Wu W, Nishikawa H, Hayami R, Oyake D, Yabuki Y, Fukuda M, Ohta T. Cancer Lett. 2006; 233(1): 108-116. Medline 15878232

BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition. Vahteristo P, Syrjakoski K, Heikkinen T, Eerola H, Aittomaki K, von Smitten K, Holli K, Blomqvist C, Kallioniemi OP, Nevanlinna H. Eur J Hum Genet. 2006; 14(2): 167-172. Medline 16333312

Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis. Wu JY, Vlastos AT, Pelte MF, Caligo MA, Bianco A, Krause KH, Laurent GJ, Irminger-Finger I. Int J Cancer. 2006; 118(5): 1215-1226. Medline 16152612

Atlas Genet Cytogenet Oncol Haematol 2007; 3 417 Ubiquitination and Proteasome-Mediated Degradation of BRCA1 and BARD1 During steroidogenesis in Human Ovarian Granulosa Cells. Lu Y, Amleh A, Sun J, Jin X, McCullough SD, Baer R, Ren D, Li R, Hu Y. Mol Endocrinol. 2007; 21(3): 651-663. Medline 17185394

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 02-2007 Irmgard Irminger-Finger Citation This paper should be referenced as such : Irminger-Finger I . BARD1 (BRCA1 associated RING domain 1). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/BARD1ID756ch2q35.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 418 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1) Identity Other names CRAF Raf-1 c-Raf Hugo RAF1 Location 3p25 DNA/RNA Note History and Nomenclature: c-Raf-1 was the first successfully cloned functional human homolog of the v-Raf gene, and thus the gene product of c-Raf-1 has historically been referred to in the literature simply as Raf-1. Subsequently, B-Raf and A-Raf-1 paralogues ( BRAF, located in Xq13 and ARAF, located in Xp11) were discovered. A suitable nomenclature is as follows: A-RAF, B-RAF, and C-RAF for the functional human proteins and A-RAF, B- RAF, and C-RAF for the corresponding genes; a-raf, b-raf, and c-raf for the murine proteins and A-Raf, B-Raf, and C-Raf for the corresponding genes. Raf-1 (or RAF-1) is generally taken to mean C-RAF-1 but could apply to A-RAF-1 equally. Here, RAF-1 will be taken to mean C-RAF-1 (RAF-1 = C-RAF-1, etc.). Description C-RAF (RAF-1, C-RAF-1) encompasses 80,570 bp of DNA; 17 Exons. Transcription RAF-1 transcribed mRNA contains 3212-3216 nucleotides. Protein Description The RAF proteins share three conserved domains: two (CR1 and CR2) in the N terminus and a third (CR3-encoding for the serine/threonine kinase domain) in the C terminus. The RAF proteins exhibit complex regulation involving numerous phosphorylation sites throughout the proteins. Despite constitutional similarity, the Raf isoforms have been shown to carry out non-redundant functions, implying that they are distinct. RAF-1 (C-RAF-1): 72-74 kDa. Note: A-RAF: about 68 kDa. Note: B-RAF (which undergoes alternate splicing): ranges from 75 to 100 kDa. Expression C-RAF (RAF-1) and A-RAF mRNA is expressed ubiquitously. A-RAF mRNA is highly expressed in urogenital organs. B-RAF is expressed in a wide range of tissues, but most substantially in neuronal tissues. Localisation Cytosolic. Function RAF proteins are part of the conserved MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling cascade between the cell surface and the nucleus. RAF is regulated by the upstream RAS family of small G proteins. RAS is predominantly located on the inner leaflet of the plasma membrane and is functionally activated by GTP-binding. Binding of various extracellular ligands such as growth factors and hormones activates RAS and subsequently RAF proteins. RAS binds directly to the N-terminal regulatory domain or RAF (the RAS binding domain (RBD)). RAS interacts secondarily with the cysteine-rich domain (CRD) on CR1 of RAF. RAS- RAF binding can be affected by 14-3-3 proteins and other scaffold/adaptor proteins kinase suppressor of RAS (KSR), the multidomain protein connector-enhancer of KSR (CNK), and the leucine-rich-repeat protein suppressor of RAS mutations-8 (SUR8), which cause formation of various homo- and heterodimers and subsequently affect signal transduction. RAF activation leads to activation of the protein kinases MEK1 and MEK2 and subsequently the MAPK proteins ERK1 and ERK2. The downstream

Atlas Genet Cytogenet Oncol Haematol 2007; 3 419 effects of MEK1/2-ERK1/2 activation are varied, complex, and depend on the cellular context. Resultant effects include activation of transcription factors involved in tumorigenesis, cell growth, survival, differentiation, metabolism, and cytoskeletal rearrangements. RAF-1 (C-RAF-1), A-RAF, and B-RAF are all capable of activating the MEK1/2-ERK1/2 signaling pathway. RAF-1 is capable of activating the NF-kB transcription factor through an unknown mechanism that does not seem to involve direct phosphorylation of NF-kB and is independent of MEK1/2-ERK1/2 signaling. RAF-1 is known to directly affect cell survival through phosphorylation of BAG1 (BCL2- associated athanogene-1), an anti-apoptotic protein that binds to BCL2, a second anti- apoptotic factor, also the prototype for a family of mammalian genes involved in mitochondrial outer membrane permeability (MOMP), thus restoring its function. BCL2 also targets RAF-1 to the mitochondrial membrane, where it is able to more readily phosphorylate substrates. The RAF-1/BAG1/BCL2 interaction allows RAF-1 to phosphorylate the pro-apoptotic protein BAD at the mitochondrial membrane, promoting cell survival. Other known substrates of RAF-1 include the phosphatase CDC25C, the apoptosis signal-regulating kinase-1 (ASK1), and the tumor-suppressor protein retinoblastoma (Rb). RAF-1 is tightly regulated by the AKT/PKB pathway through phosphorylation at S259. Mutations Somatic It has been widely established that RAF-1 over activity, typically via ras-activating mutations, is central to tumorigenesis and cell proliferation in numerous cancers (about 30% of all human cancers). However, it has come to the fore that oncogenesis may be due to ras/RAF-1 dysregulation (either increased or decreased expression) rather than increases in ras/RAF-1 activity exclusively. Implicated in Entity Medullary Thyroid Cancer (MTC) Disease A neuroendocrine tumor derived from parafollicular C cells of the thyroid gland, MTC is the third most common form of thyroid cancer, accounting for 3-5% of all cases. MTC cells secrete hormones and tumor markers such as calcitonin, chromogranin A (CgA), and carcinoembryonic antigen (CEA). Symptoms are related to either direct invasion or metastasis (neck mass, dyspnea, dysphagia, voice changes, pain) or tumor secretion of bioactive amines and peptides (diarrhea, flushing). Prognosis Currently, surgery is the only potentially curative therapy for patients with MTC. The recommended operation is total thyroidectomy with lymph node dissection. However, 50% of patients treated with surgery suffer persistent or recurrent disease. Oncogenesis 20% of patients with medullary thyroid cancer have an autosomal dominant inherited form of the disease, which is the result of well-characterized point mutations in the RET proto-oncogene. RAF-1 is conserved but not expressed at baseline in MTC. Pre- clinical studies have shown that activation of RAF-1 in MTC (TT) cells by means of RAF-1 gene transfection or RAF-1 activating small molecules (ZM336372) results in tumor cell growth inhibition in vitro and in vivo.

Entity Carcinoid Tumors Disease Carcinoids are tumors that arise from the diffuse neuroendocrine cell system of the gut, lungs, and other organs. The incidence is 1-5 per 100,000 individuals. Carcinoids frequently metastasize to the liver and are the second most common source of isolated liver metastases. Carcinoids secrete various bioactive hormones such as 5-HT (5- hydroxy tryptophan, also known as serotonin) and chromogranin A. Prognosis Patients with hepatic metastases suffer debilitating symptoms such as abdominal pain, flushing, bronchoconstriction, and diarrhea. Palliative treatment for these hormone- induced symptoms includes somatostatin analogs (such as octeotride). Conventional anticancer treatments such as chemotherapy and external beam radiation is largely

Atlas Genet Cytogenet Oncol Haematol 2007; 3 420 ineffective for carcinoid tumors. Oncogenesis RAF-1 activation is detrimental to tumorigenesis in carcinoid cells. Marked reduction in neuroendocrine phenotypic markers such as human achaete-scute complex like-1 (ASCL-1) and bioactive hormones 5-HT, chromogranin A, and synaptophysin has been noted upon RAF-1 activation using an estrogen-inducible RAF-1 construct in human GI (BON) and pulmonary carcinoid cell lines (NCI-H727) . Treatment of GI carcinoid cells with RAF-1 activator ZM336372 led to a decrease in bioactive hormone levels, a suppression of cellular proliferation, an increase in cell cycle inhibitors p21 and p18, as well as a decrease in the neuroendocrine phenotypic marker ASCL-1. ZM336372 treatments also led to progressive phosphorylation (activation) of MEK1/2, ERK1/2, and RAF-1.

Entity Small Cell Lung Cancer (SCLC) Disease SCLC tends to present with metastatic and regional spread. Carcinoids rarely metastasize, arise from major bronchi, and express neuron-specific enolase, chromogranin, and synaptophysin. Neuroendocrine carcinoids or atypical carcinoids have a more aggressive course. Oncogenesis Human small-cell lung cancer (SCLC) cell lines rarely harbor ras-activating mutations. In one cell line of SCLC, DMS53, it was shown that by RAF-1 induction using an estrogen-inducible RAF-1 construct SCLC cells underwent differentiation and G1- specific growth arrest in conjunction with MEK/ERK1/2 pathway activation.

Entity Non-Small Cell Lung Cancer (NSCLC). Disease Adenocarcinoma is the most common type of NSCLC accounting for about 40% of cases. Lesions are generally located peripherally and develop systemic metastases despite small primary tumors. 25% of NSCLC are squamous cell carcinomas which often remain localized. Oncogenesis RAF-1 is over-expressed due to oncogenic ras mutations in about 35% of NSCLC. The majority of NSCLC exhibits EGFR over-expression leading to upregulation of RAF-1 activity. NSCLC has been shown to be mediated by a TGF-a/EGFR-mediated autocrine loop activated by signaling involving RAF-1 and PI3K-Akt.

Entity Pheochromocytoma. Disease Pheochromocytomas are neuroectodermal in origin and arise from the chromaffin cells of the adrenal medulla. 10% of tumors are bilateral. Typical symptoms such as hypertension, headaches, diaphoresis, palpitations, diarrhea, and skin rashes, are related to tumor production of catecholamines, especially in patients with metastases. Pheochromocytoma is potentially fatal, but relatively uncommon (2-8 cases per million people annually). Curative therapy is surgery, usually accomplished by laparoscopic adrenalectomy. Oncogenesis Activation of MEK1/2-ERK1/2 is necessary for differentiation of pheochromocytoma (PC12) cells and leads to decreased cell proliferation. RAF-1 activation in pheochromocytoma cells using ZM336372 led to cellular differentiation, growth arrest, and a decrease in the neuroendocrine marker chromogranin A.

Entity Non-Neuroendocrine Cancers with ras-activating Mutations. Oncogenesis About 30% of all human cancers express ras-activating mutations. More than 85% of pancreatic adenocarcinomas, and 50% of colonic adenocarcinomas harbor K-ras mutations. K-ras is an upstream effector of RAF-1 in the RAF-1/MEK/ERK1/2 signaling pathway. Ras mutations have also been linked to tumorigenesis of cholangiocarcinoma, adenocarcinoma of the lung, squamous cell cancer, gastric adenocarcinoma, small bowel adenocarcinoma, and malignant melanoma.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 421 Entity Colorectal Cancer. Oncogenesis RAF-1 is over-activated due to oncogenic ras mutations in about 50% of colon cancers. These mutations are associated with poor prognosis, and are necessary for maintenance of the malignant phenotype. RAF-1 inhibition in response to interaction with RAF kinase inhibitor protein (RKIP) (up-regulated in conjunction with the nuclear factor kappa B signaling pathway) has been linked with overall and disease-free survival in patients with colorectal cancers. RKIP has been identified as potentially useful for identifying early-stage CRC patients at risk for relapse.

Entity Pancreatic Carcinoma. Oncogenesis RAF-1 is overactivated due to oncogenic ras mutations in about 90% of pancreatic carcinomas (Panc-1 and Mia-PaCa2). It has been shown that malignancy of these cells is reduced using k-ras RNAi. Pharmacological inhibition of the RAF/MEK/ERK pathway in pancreatic cancer cell lines (via MEK inhibition) results in reduction in cellular proliferation and an increase in cell cycle arrest.

Entity Hepatocellular Carcinoma (HCC) Oncogenesis RAF-1 is over-activated in about 50% of biopsies while the RAF-1 protein is over- expressed in nearly 100% of all HCC's. Angiogenesis and other functions essential to tumorigenesis in HCC have been reported to depend on the RAF/MEK/ERK signaling pathway. RAF-1 inhibitor Sorafenib has been reported (in-vitro and in-vivo) to inhibit RAF-1 activity, leading to decreased MEK/ERK activity, reduced cellular proliferation, and apoptosis in several HCC cell lines including HepG2 and PLC/PRF/5.

Entity Prostate Cancer. Oncogenesis RAF kinase inhibitor protein (RKIP) coding mRNAs have been observed to activate interferon-inducible 2',5'-oligoadenylate synthetases (OAS). OAS activity is characteristically increased (via these mRNAs) in prostate cancer cell lines PC3, LNCaP and DU145. RKIP expression is detectable in primary prostate cancer sections but not in metastases. This suggests RKIP's characterization as an anti-metastasis gene using the RAF/MEK/ERK signaling pathway is appropriate. RAF-1 inhibition using systemically delivered novel cationic cardiolipin liposomes (NeoPhectin-AT) containing a small interfering RNA (siRNA) against RAF-1 causes tumor growth inhibition in a xenograft model of human prostate cancer. RAF/MEK/ERK signaling pathway activation via a biologically active peptide called a prosaptide (TX14A) stimulates cell proliferation/survival, migration, and invasion in human prostate cancer cells. NSC 95397 and NSC 672121, cdc25 inhibitors, were shown to activate the RAF/MEK/ERK pathway in prostate cancer cells. RAF-1 activation in LNCaP prostate cancer cells using an estrogen-inducible construct led to growth inhibition.

Entity Breast Cancer. Oncogenesis Growth hormone releasing hormone has been shown to regulate breast cancer cell proliferation and differentiation. In MDA-231 breast cancer cells, exogenous GHRH stimulated dose-dependent proliferation. RAF-1 inhibition using the agent PD98059 caused prevention of MAPK phosphorylation by GHRH as well as reduced cellular proliferation. ONCOGENESIS Proliferative effects of steroid hormone estradiol on MCF-7 breast cancer cells have been linked with increased expression of RAF-1, possibly due to direct activation of RAF-1 by estradiol. RAF kinase inhibitor protein (RKIP) is associated with metastasis suppression. RKIP expression is lost in lymph node metastases. This suggests RKIP is a metastasis inhibitor gene and that RAF-1 expression enables metastasis.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 422 The PTK inhibitor AG 879 inhibits proliferation of human breast cancer cells through inhibition of MAP kinase activation through inhibition of expression of the RAF-1 gene. RAF-1 down-regulation is associated with paclitaxel drug resistance in human breast cancer cell line MCF-7/Adr.

Entity Renal Cell Carcinoma. Oncogenesis RAF-1 is overactivated in conjunction with loss of function of the VHL ( von Hippel- Lindau) tumor-suppressor gene.

Entity Glioma . Oncogenesis RAF-1 inhibitor AAL881 inhibited growth of glioma cell xenografts.

Entity Cervical Cancer. Oncogenesis Low RAF-1 kinase activity is significantly associated with paclitaxel sensitivity in cervical cancers.

Entity Ovarian Cancer. Oncogenesis RAF-1 dysregulation is associated with poor prognosis and possibly carcinogenesis. RAF-1 inhibition using RNAi reduces cellular proliferatin and inhibits ovarian tumor cell growth in vitro and in vivo. Similar results were observed using antisense oligonucleotide (ASO) therapy (ISIS 5132 and ISIS 13650). RAF-1 inhibition by the Akt pathway sensitizes human ovarian cancer cells to the drug paclitaxel.

Entity Gastric Cancer. Oncogenesis RAF-1 inactivation using RNAi in gastric cancer cell line SGC7901 led to dramatic reductions in angiogenesis, increased apoptosis, and decreased cellular proliferation.

Entity Bladder Cancer. Oncogenesis RAF-1 gene amplification was detected in 4% of bladder cancer samples. Deletions at the RAF-1 locus were detected in 2.2% of these samples. Both amplifications and deletions were heavily correlated with high tumor grade (P < 0.00001), advanced stage (P < 0.0001), and poor survival (P<0.05).

Entity Lymphoma. Oncogenesis RAF-1 is typically over-expressed in thymic lymphomas from TCR transgenic mice. External links Nomenclature Hugo RAF1 GDB RAF1 Entrez_Gene RAF1 5894 v-raf-1 murine leukemia viral oncogene homolog 1 Cards Atlas RAF1ID42032ch3p25 GeneCards RAF1 Ensembl RAF1 Genatlas RAF1 GeneLynx RAF1

Atlas Genet Cytogenet Oncol Haematol 2007; 3 423 eGenome RAF1 euGene 5894 Genomic and cartography GoldenPath RAF1 - 3p25 chr3:12600108-12680678 - 3p25 (hg18-Mar_2006) Ensembl RAF1 - 3p25 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene RAF1 Gene and transcription Genbank AK226028 [ ENTREZ ] Genbank BC018119 [ ENTREZ ] Genbank BQ221862 [ ENTREZ ] Genbank CR598160 [ ENTREZ ] Genbank CR608506 [ ENTREZ ] RefSeq NM_002880 [ SRS ] NM_002880 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_022517 [ SRS ] NT_022517 [ ENTREZ ] RefSeq NW_921651 [ SRS ] NW_921651 [ ENTREZ ] AceView RAF1 AceView - NCBI Unigene Hs.159130 [ SRS ] Hs.159130 [ NCBI ] HS159130 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P04049 [ SRS] P04049 [ EXPASY ] P04049 [ INTERPRO ] PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP [ Prosite Expasy ] PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM [ Prosite Expasy ] PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 PROTEIN_KINASE_ST [ Prosite Expasy ] Prosite PS50898 RBD [ SRS ] PS50898 RBD [ Expasy ] Prosite PS00479 ZF_DAG_PE_1 [ SRS ] PS00479 ZF_DAG_PE_1 [ Expasy ] Prosite PS50081 ZF_DAG_PE_2 [ SRS ] PS50081 ZF_DAG_PE_2 [ Expasy ] Interpro IPR002219 DAG_PE_bd [ SRS ] IPR002219 DAG_PE_bd [ EBI ] Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ] Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR003116 Raf_like_ras_bd [ SRS ] IPR003116 Raf_like_ras_bd [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ] CluSTr P04049 Pfam PF00130 C1_1 [ SRS ] PF00130 C1_1 [ Sanger ] pfam00130 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI-CDD ] Pfam PF02196 RBD [ SRS ] PF02196 RBD [ Sanger ] pfam02196 [ NCBI-CDD ] Smart SM00109 C1 [EMBL] Smart SM00455 RBD [EMBL] Prodom PD000001 Prot_kinase[INRA-Toulouse]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 424 P04049 RAF1_HUMAN [ Domain structure ] P04049 RAF1_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P04049 PDB 1C1Y [ SRS ] 1C1Y [ PdbSum ], 1C1Y [ IMB ] 1C1Y [ RSDB ] PDB 1FAQ [ SRS ] 1FAQ [ PdbSum ], 1FAQ [ IMB ] 1FAQ [ RSDB ] PDB 1FAR [ SRS ] 1FAR [ PdbSum ], 1FAR [ IMB ] 1FAR [ RSDB ] PDB 1GUA [ SRS ] 1GUA [ PdbSum ], 1GUA [ IMB ] 1GUA [ RSDB ] PDB 1RFA [ SRS ] 1RFA [ PdbSum ], 1RFA [ IMB ] 1RFA [ RSDB ] HPRD P04049 Protein Interaction databases DIP P04049 IntAct P04049 Polymorphism : SNP, mutations, diseases OMIM 164760 [ map ] GENECLINICS 164760 SNP RAF1 [dbSNP-NCBI] SNP NM_002880 [SNP-NCI] SNP RAF1 [GeneSNPs - Utah] RAF1] [HGBASE - SRS] HAPMAP RAF1 [HAPMAP] COSMIC RAF1 [Somatic mutation (COSMIC-CGP-Sanger)] General knowledge Family RAF1 [UCSC Family Browser] Browser SOURCE NM_002880 SMD Hs.159130 SAGE Hs.159130 2.7.11.1 [ Enzyme-SRS ] 2.7.11.1 [ Brenda-SRS ] 2.7.11.1 [ KEGG ] 2.7.11.1 [ Enzyme WIT ] GO nucleotide binding [Amigo] nucleotide binding protein serine/threonine kinase activity [Amigo] protein serine/threonine kinase GO activity GO receptor signaling protein activity [Amigo] receptor signaling protein activity GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO mitochondrial outer membrane [Amigo] mitochondrial outer membrane GO protein amino acid phosphorylation [Amigo] protein amino acid phosphorylation GO apoptosis [Amigo] apoptosis cytoskeleton organization and biogenesis [Amigo] cytoskeleton organization and GO biogenesis GO intracellular signaling cascade [Amigo] intracellular signaling cascade GO zinc ion binding [Amigo] zinc ion binding GO cell proliferation [Amigo] cell proliferation GO transferase activity [Amigo] transferase activity GO diacylglycerol binding [Amigo] diacylglycerol binding GO metal ion binding [Amigo] metal ion binding

Atlas Genet Cytogenet Oncol Haematol 2007; 3 425 Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent BIOCARTA signaling [Genes] BIOCARTA CCR3 signaling in Eosinophils [Genes] BIOCARTA Influence of Ras and Rho proteins on G1 to S Transition [Genes] BIOCARTA TPO Signaling Pathway [Genes] Roles of ß-arrestin-dependent Recruitment of Src Kinases in GPCR BIOCARTA Signaling [Genes] BIOCARTA Role of ß-arrestins in the activation and targeting of MAP kinases [Genes] BIOCARTA BCR Signaling Pathway [Genes] BIOCARTA Bioactive Peptide Induced Signaling Pathway [Genes] BIOCARTA Cadmium induces DNA synthesis and proliferation in macrophages [Genes] Phosphorylation of MEK1 by cdk5/p35 down regulates the MAP kinase BIOCARTA pathway [Genes] BIOCARTA Ceramide Signaling Pathway [Genes] BIOCARTA CXCR4 Signaling Pathway [Genes] Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal BIOCARTA Epithelia [Genes] BIOCARTA EGF Signaling Pathway [Genes] BIOCARTA EPO Signaling Pathway [Genes] BIOCARTA Erk1/Erk2 Mapk Signaling pathway [Genes] BIOCARTA fMLP induced chemokine gene expression in HMC-1 cells [Genes] BIOCARTA Fc Epsilon Receptor I Signaling in Mast Cells [Genes] BIOCARTA Growth Hormone Signaling Pathway [Genes] BIOCARTA Inhibition of Cellular Proliferation by Gleevec [Genes] BIOCARTA Signaling Pathway from G-Protein Families [Genes] BIOCARTA Role of ERBB2 in Signal Transduction and Oncology [Genes] BIOCARTA IGF-1 Signaling Pathway [Genes] Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD BIOCARTA phosphorylation [Genes] BIOCARTA IL 2 signaling pathway [Genes] BIOCARTA IL-2 Receptor Beta Chain in T cell Activation [Genes] BIOCARTA IL 3 signaling pathway [Genes] BIOCARTA IL 6 signaling pathway [Genes] BIOCARTA Insulin Signaling Pathway [Genes] BIOCARTA Integrin Signaling Pathway [Genes] BIOCARTA Keratinocyte Differentiation [Genes] BIOCARTA Role of MAL in Rho-Mediated Activation of SRF [Genes] BIOCARTA MAPKinase Signaling Pathway [Genes] BIOCARTA Signaling of Hepatocyte Growth Factor Receptor [Genes] BIOCARTA NFAT and Hypertrophy of the heart (Transcription in the broken heart) [Genes] BIOCARTA Nerve growth factor pathway (NGF) [Genes] BIOCARTA PDGF Signaling Pathway [Genes] BIOCARTA Links between Pyk2 and Map Kinases [Genes] BIOCARTA Ras Signaling Pathway [Genes] BIOCARTA Aspirin Blocks Signaling Pathway Involved in Platelet Activation [Genes]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 426 BIOCARTA Sprouty regulation of tyrosine kinase signals [Genes] BIOCARTA T Cell Receptor Signaling Pathway [Genes] PubGene RAF1 Other databases Probes Probe RAF1 Related clones (RZPD - Berlin) PubMed PubMed 198 Pubmed reference(s) in LocusLink Bibliography Structure and biological activity of human homologs of the raf/mil oncogene. Bonner TI, Kerby SB, Sutrave P, Gunnell MA, Mark G, Rapp UR. Mol Cell Biol. 1985; 5(6):1400-1407. Medline 2993863

Actively transcribed genes in the raf oncogene group, located on the X chromosome in mouse and human. Huebner K, ar-Rushdi A, Griffin CA, Isobe M, Kozak C, Emanuel BS, Nagarajan L, Cleveland JL, Bonner TI, Goldsborough MD, et al. Proc Natl Acad Sci U S A. 1986; 83(11):3934-3938. Medline 3520560

The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. Beck TW, Huleihel M, Gunnell M, Bonner TI, Rapp UR. Nucleic Acids Res. 1987; 15(2):595-609. Medline 3029685

Expression of raf family proto-oncogenes in normal mouse tissues. Storm SM, Cleveland JL, Rapp UR. Oncogene 1990; 5(3):345-351. Medline 1690378

MAP kinases ERK1 and ERK2: pleiotropic enzymes in a ubiquitous signaling network. Robbins DJ, Zhen E, Cheng M, Xu S, Ebert D, Cobb MH. Adv Cancer Res. 1994; 63:93-116. Medline 8036991

The mouse B-raf gene encodes multiple protein isoforms with tissue-specific expression. Barnier J, Papin C, Eychene A, Lecoq O, Calothy G. The Journal of Biological Chemistry 1995; 270(40):23381-23389. Medline 7559496

Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation. Galaktionov K, Jessus C, Beach D. Genes Dev. 1995; 9(9):1046-1058. Medline 7744247

Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene. Pritchard CA, Bolin L, Slattery R, Murray R, McMahon M. Curr Biol. 1996; 6(5):614-617.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 427 Medline 8805280

Bcl-2 targets the protein kinase Raf-1 to mitochondria. Wang HG, Rapp UR, Reed JC. Cell. 1996; 87(4):629-638. Medline 8929532

Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. Wang HG, Takayama S, Rapp UR, Reed JC. Proc Natl Acad Sci U S A. 1996; 93(14):7063-7068. Medline 8692945

How Ras-related proteins talk to their effectors. Wittinghofer A, Nassar N. Trends Biochem Sci. 1996; 21(12):488-491. Medline 9009833

Endothelial apoptosis in Braf-deficient mice. Wojnowski L, Zimmer AM, Beck TW, Hahn H, Bernal R, Rapp UR, Zimmer A. Nat Genet. 1997; 16(3):293-297. Medline 9207797

Paclitaxel is preferentially cytotoxic to human cervical tumor cells with low Raf-1 kinase activity: implications for paclitaxel-based chemoradiation regimens. Britten RA, Perdue S, Opoku J, Craighead P. Radiother Oncol. 1998; 48(3):329-334. Medline 9925253

Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Denouel-Galy A, Douville EM, Warne PH, Papin C, Laugier D, Calothy G, Downward J, Eychene A. Curr Biol. 1998; 8(1):46-55. Medline 9427625

Estrogen activates raf-1 kinase and induces expression of Egr-1 in MCF-7 breast cancer cells. Pratt MA, Satkunaratnam A, Novosad DM. Mol Cell Biochem. 1998; 189(1-2):119-125. Medline 9879662

Craf-1 protein kinase is essential for mouse development. Wojnowski L, Stancato LF, Zimmer AM, Hahn H, Beck TW, Larner AC, Rapp UR, Zimmer A. Mech Dev. 1998; 76(1-2):141-149. Medline 9767153

Raf-1 physically interacts with Rb and regulates its function: a link between mitogenic signaling and cell cycle regulation. Wang S, Ghosh RN, Chellappan SP. Mol Cell Biol. 1998; 18(12):7487-798. Medline 9819434

Raf-1-induced cell cycle arrest in LNCaP human prostate cancer cells. Ravi RK, McMahon M, Yangang Z, Williams JR, Dillehay LE, Nelkin BD, Mabry M. J Cell Biochem. 1999; 72(4):458-69. Medline 10022606

Atlas Genet Cytogenet Oncol Haematol 2007; 3 428 Phosphorylation and regulation of Raf by Akt (protein kinase B). Zimmermann S, Moelling K. Science. 1999; 286(5445):1741-1744. Medline 10576742

Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. Baumann B, Weber CK, Troppmair J, Whiteside S, Israel A, Rapp UR, Wirth T. Proc Natl Acad Sci U S A. 2000; 97(9):4615-4620. Medline 10758165

Overexpression of Ras, Raf and L-myc but not Bcl-2 family proteins is linked with resistance to TCR-mediated apoptosis and tumorigenesis in thymic lymphomas from TCR transgenic mice. Kobzdej M, Matuszyk J, Strzadala L. Leuk Res. 2000; 24(1):33-38. Medline 10634643

The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf. Li W, Han M, Guan KL. Genes Dev. 2000; 14(8):895-900. Medline 10783161

Expression of the A-raf proto-oncogene in the normal adult and embryonic mouse. Luckett JC, Huser MB, Giagtzoglou N, Brown JE, Pritchard CA. Cell Growth Differ. 2000; 11(3):163-171. Medline 10768864

Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Chen J, Fujii K, Zhang L, Roberts T, Fu H. Proc Natl Acad Sci U S A. 2001; 98(14):7783-7788. Medline 11427728

KSR: a MAPK scaffold of the Ras pathway? Morrison DK. J Cell Sci. 2001; 114(Pt 9):1609-1612. Medline 11309192

MEK kinase activity is not necessary for Raf-1 function. Huser M, Luckett J, Chiloeches A, Mercer K, Iwobi M, Giblett S, Sun XM, Brown J, Marais R, Pritchard C. EMBO J. 2001; 20(8):1940-1951. Medline 11296227

Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer. McPhillips F, Mullen P, Monia BP, Ritchie AA, Dorr FA, Smyth JF, Langdon SP. Br J Cancer. 2001; 85(11):1753-1758. Medline 11742498

Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. Mikula M,Schreiber M,Husak Z,Kucerova L,Ruth J,Wieser R,Zatloukal K,Beug H,Wagner EF,Baccarini M.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 429 EMBO J. 2001; 20(8):1952-1962. Medline 11296228

High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer. Simon R, Richter J, Wagner U, Fijan A, Bruderer J, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Wilber K, Anabitarte M, Hering F, Hardmeier T, Schonenberger A, Flury R, Jager P, Fehr JL, Schraml P, Moch H, Mihatsch MJ, Gasser T, Sauter G. Cancer Res. 2001; 61(11):4514-4519. Medline 11389083

Critical contribution of linker proteins to Raf kinase activation. Anselmo AN, Bumeister R, Thomas JM, White MA. J Biol Chem. 2002; 277(8):5940-5943. Medline 11741918

Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. Mabuchi S, Ohmichi M, Kimura A, Hisamoto K, Hayakawa J, Nishio Y, Adachi K, Takahashi K, Arimoto-Ishida E, Nakatsuji Y, Tasaka K, Murata Y. J Biol Chem. 2002; 277(36):33490-33500. Medline 12087097

Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. Pouyssegur J, Volmat V, Lenormand P. Biochem Pharmacol. 2002; 64(5-6):755-763. Medline 12213567

Activation of the ras/raf-1 signal transduction pathway in carcinoid tumor cells results in morphologic transdifferentiation. Sippel RS, Chen H. Surgery. 2002; 132(6):1035-1039. Medline 12490852

14-3-3 proteins: active cofactors in cellular regulation by serine/threonine phosphorylation. Tzivion G, Avruch J. J Biol Chem. 2002; 277(5):3061-3064. Medline 11709560

The effects of beta-estradiol on Raf activity, cell cycle progression and growth factor synthesis in the MCF-7 breast cancer cell line. Weinstein-Oppenheimer CR, Burrows C, Steelman LS, McCubrey JA. Cancer Biol Ther. 2002; 1(3):256-262. Medline 12432273

Raf-1 and Bcl-2 induce distinct and common pathways that contribute to breast cancer drug resistance. Davis JM, Navolanic PM, Weinstein-Oppenheimer CR, Steelman LS, Hu W, Konopleva M, Blagosklonny MV, McCubrey JA. Clin Cancer Res. 2003; 9(3):1161-1170. Medline 12631622

Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z, Keller ET.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 430 J Natl Cancer Inst. 2003; 95(12):878-889. Medline 12813171

Ras proteins: different signals from different locations. Hancock JF. Nat Rev Mol Cell Biol. 2003; 4(5):373-384. Medline 12728271

Down-regulation of Raf-1 kinase is associated with paclitaxel resistance in human breast cancer MCF-7/Adr cells. Lee M, Koh WS, Han SS. Cancer Lett. 2003; 193(1):57-64. Medline 12691824

Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf. Lanigan TM,Liu A,Huang YZ,Mei L,Margolis B,Guan KL. FASEB J. 2003; 17(14):2048-2060. Medline 14597674

Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Morrison DK, Davis RJ. Annu Rev Cell Dev Biol. 2003; 19:91-118. Review. Medline 14570565

Raf-1 activation suppresses neuroendocrine marker and hormone levels in human gastrointestinal carcinoid cells. Sippel R.S., Carpenter J.E., Kunnimalaiyaan M., Lagerholm S., Chen H. Am.J.Physiol.Gastrointest.Liver Physiol. 2003; 285, 2: G245-254. Medline 12851216

Raf and the road to cell survival: a tale of bad spells, ring bearers and detours. Troppmair J, Rapp UR. Biochem Pharmacol. 2003; 66(8):1341-1345. Medline 14555207

Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene. Keller ET, Fu Z, Yeung K, Brennan M. Cancer Lett. 2004; 207(2):131-137. Medline 15151133

Prosaptide TX14A stimulates growth, migration, and invasion and activates the Raf-MEK-ERK- RSK-Elk-1 signaling pathway in prostate cancer cells. Koochekpour S, Sartor O, Lee TJ, Zieske A, Patten DY, Hiraiwa M, Sandhoff K, Remmel N, Minokadeh A. Prostate. 2004; 61(2):114-123. Medline 15305334

Novel actions of tyrphostin AG 879: inhibition of RAF-1 and HER-2 expression combined with strong antitumoral effects on breast cancer cells. Larsson LI. Cell Mol Life Sci. 2004; 61(19-20):2624-2631. Medline 15526167

Antisense oligonucleotide targeting of Raf-1: importance of raf-1 mRNA expression levels and

Atlas Genet Cytogenet Oncol Haematol 2007; 3 431 raf-1-dependent signaling in determining growth response in ovarian cancer. Mullen P, McPhillips F, MacLeod K, Monia B, Smyth JF, Langdon SP. Clin Cancer Res. 2004; 10(6):2100-2108. Medline 15041731

Activation of the Raf-1/MEK/Erk kinase pathway by a novel Cdc25 inhibitor in human prostate cancer cells. Nemoto K, Vogt A, Oguri T, Lazo JS. Prostate. 2004; 58(1):95-102. Medline 14673957

The RAF proteins take center stage. Wellbrock C, Karasarides M, R Marais. Nature Reviews Molecular Cell Biology 2004; 5(11):875-885. Medline 15520807

Medullary thyroid cancer: the functions of raf-1 and human achaete-scute homologue-1. Chen H, Kunnimalaiyaan M, Van Gompel JJ. Thyroid 2005; 15, 6: 511-521. Medline 16029117

Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Gysin S, Lee SH, Dean NM, McMahon M. Cancer Res. 2005; 65(11):4870-4880. Medline 15930308

Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. Hagan S, Al-Mulla F, Mallon E, Oien K, Ferrier R, Gusterson B, Garcia JJ, Kolch W. Clin Cancer Res. 2005; 11(20):7392-7397. Medline 16243812

Inhibition of gastric cancer angiogenesis by vector-based RNA interference for Raf-1. Meng F, Ding J, Liu N, Zhang J, Shao X, Shen H, Xue Y, Xie H, Fan D. Cancer Biol Ther. 2005; 4(1):113-117. Medline 15662129

Systemic delivery of Raf siRNA using cationic cardiolipin liposomes silences Raf-1 expression and inhibits tumor growth in xenograft model of human prostate cancer. Pal A, Ahmad A, Khan S, Sakabe I, Zhang C, Kasid UN, Ahmad I. Int J Oncol. 2005; 26(4):1087-1091. Medline 15754006

ZM336372, a Raf-1 activator, suppresses growth and neuroendocrine hormone levels in carcinoid tumor cells Van Gompel J.J., Kunnimalaiyaan M, Holen K, Chen H. Mol.Cancer.Ther. 2005; 4, 6: 910-917. Medline 15956248

Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients. Al-Mulla F,Hagan S,Behbehani AI,Bitar MS,George SS,Going JJ,Garcia JJ,Scott L,Fyfe N,Murray GI,Kolch W. J Clin Oncol. 2006; 24(36):5672-5679.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 432 Medline 17179102

Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. Fu Z, Kitagawa Y, Shen R, Shah R, Mehra R, Rhodes D, Keller PJ, Mizokami A, Dunn R, Chinnaiyan AM, Yao Z, Keller ET. Prostate. 2006; 66(3):248-256. Medline 16175585

Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Gollob JA,Wilhelm S,Carter C,Kelley SL. Semin Oncol. 2006; 33(4):392-406. Medline 16890795

ZM336372, a Raf-1 activator, inhibits growth of pheochromocytoma cells. Kappes A, Vaccaro A, Kunnimalaiyaan M, Chen H. J.Surg.Res. 2006; 133 (1): 42-45. Medline 16603190

The Raf-1 pathway: a molecular target for treatment of select neuroendocrine tumors? Kunnimalaiyaan M, Chen H. Anticancer Drugs 2006; 17, 2: 139-142. Medline 16428931

Transforming growth factor-beta1 sensitivity is altered in Abl-Myc- and Raf-Myc-induced mouse pre-B-cell tumors. Letterio J,Rudikoff E,Voong N,Bauer SR. Stem Cells. 2006; 24(12):2611-2617. Medline 16945999

Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. Cancer Res. 2006; 66(24):11851-11858. Medline 17178882

Selection and cloning of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2',5'-oligoadenylate synthetase from prostate cancer cells. Molinaro RJ, Jha BK, Malathi K, Varambally S, Chinnaiyan AM, Silverman RH. Nucleic Acids Res. 2006; 34(22):6684-6695. Medline 17145707

Comparison of strategies targeting Raf-1 mRNA in ovarian cancer. Mullen P, McPhillips F, Monia BP, Smyth JF, Langdon SP. Int J Cancer. 2006; 118(6):1565-1571. Medline 16184551

AAL881, a Novel Small Molecule Inhibitor of RAF and Vascular Endothelial Growth Factor Receptor Activities, Blocks the Growth of Malignant Glioma. Sathornsumetee S, Hjelmeland AB, Keir ST, McLendon RE, Batt D, Ramsey T, Yusuff N,Rasheed BK, Kieran MW, Laforme A, Bigner DD, Friedman HS, Rich JN. Cancer Res. 2006; 66(17):8722-8730. Medline 16951188

Atlas Genet Cytogenet Oncol Haematol 2007; 3 433

Autocrine/paracrine regulation of breast cancer cell proliferation by growth hormone releasing hormone via Ras, Raf, and mitogen-activated protein kinase. Siriwardana G,Bradford A,Coy D,Zeitler P. Mol Endocrinol. 2006; 20(9):2010-2019. Medline 16613992

In-vivo activation of Raf-1 inhibits tumor growth and development in a xenograft model of human medullary thyroid cancer. Vaccaro A, Chen H, Kunnimalaiyaan M. Anticancer Drugs 2006; 17, 7: 849-853. Medline 16926634

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written Max Cayo, David Yu Greentblatt, Muthusamy Kunnimalaiyaan, Herbert 03-2007 Chen Citation This paper should be referenced as such : Cayo M, Greentblatt DY, Kunnimalaiyaan M, Chen H . RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1). Atlas Genet Cytogenet Oncol Haematol. March 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RAF1ID42032ch3p25.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 434 Atlas of Genetics and Cytogenetics in Oncology and Haematology

PSIP1 (PC4 and SFRS1 interacting protein 1) Identity Other names LEDGF (lens epithelium-derived growth factor) p75 p52 Hugo PSIP1 Location 9p22.3 DNA/RNA Description The gene contains at least 15 exons and 14 introns. Transcription Two alternative splice variants: p75 and p52. Protein Description 530 amino acids (p75), 333 amino acids (p52); N-term - PWWP (proline-tryptophan- tryptophan-proline) domain NLS (nuclear localization signal) AT-hook-like Coiled coil IBD (integrase binding domain) HTH1 (helix-turn-helix DNA binding motif) HTH2 C- term. Expression Expression of PSIP1 has been reported to be increased in human breast and bladder cancer, prostate tumorsand benign prostate hyperplasia. Localisation nuclear. Function Transcriptional regulation of stress-associated genes, mRNA splicing and cell survival. The involvement of PSIP1 (LEDGF) has been reported in human immunodeficiency virus type-1 (HIV-1) integration, autoimmune disorders, and neurogenesis. Recent data reveal LEDGF as an oncogenic protein that controls a caspase-independent lysosomal cell death pathway. Homology PSIP1 belongs to the hepatoma-derived growth factor (HDGF) family of proteins that contain a well conserved N-terminal amino acid sequence known as the HATH (homologous to amino terminus of HDGF) region. Implicated in Entity t(9;11)(p22;p15) NUP98-PSIP1 Note acute non lymphoblastic leukemia (ANLL), one case of transformed . Hybrid/Mutated 5' NUP98 - 3' PSIP1. Gene Abnormal Fuses the GLFG repeat domains of NUP98 to the COOH-terminus of PSIP1. Protein External links Nomenclature Hugo PSIP1 GDB PSIP1 Entrez_Gene PSIP1 11168 PC4 and SFRS1 interacting protein 1 Cards Atlas PSIP1ID405ch9q22 GeneCards PSIP1 Ensembl PSIP1

Atlas Genet Cytogenet Oncol Haematol 2007; 3 435 Genatlas PSIP1 GeneLynx PSIP1 eGenome PSIP1 euGene 11168 Genomic and cartography GoldenPath PSIP1 - 9p22.3 chr9:15460644-15500250 - 9p22.3 (hg18-Mar_2006) Ensembl PSIP1 - 9p22.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PSIP1 Gene and transcription Genbank AF063020 [ ENTREZ ] Genbank AF098482 [ ENTREZ ] Genbank AF098483 [ ENTREZ ] Genbank AF432220 [ ENTREZ ] Genbank BC013160 [ ENTREZ ] RefSeq NM_021144 [ SRS ] NM_021144 [ ENTREZ ] RefSeq NM_033222 [ SRS ] NM_033222 [ ENTREZ ] RefSeq AC_000052 [ SRS ] AC_000052 [ ENTREZ ] RefSeq NC_000009 [ SRS ] NC_000009 [ ENTREZ ] RefSeq NT_008413 [ SRS ] NT_008413 [ ENTREZ ] RefSeq NW_924062 [ SRS ] NW_924062 [ ENTREZ ] AceView PSIP1 AceView - NCBI Unigene Hs.658434 [ SRS ] Hs.658434 [ NCBI ] HS658434 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O75475 [ SRS] O75475 [ EXPASY ] O75475 [ INTERPRO ] Prosite PS50812 PWWP [ SRS ] PS50812 PWWP [ Expasy ] Interpro IPR000637 AT_hook_DNA_bd [ SRS ] IPR000637 AT_hook_DNA_bd [ EBI ] Interpro IPR000313 PWWP [ SRS ] IPR000313 PWWP [ EBI ] CluSTr O75475 Pfam PF00855 PWWP [ SRS ] PF00855 PWWP [ Sanger ] pfam00855 [ NCBI-CDD ] Smart SM00293 PWWP [EMBL] Blocks O75475 PDB 1Z9E [ SRS ] 1Z9E [ PdbSum ], 1Z9E [ IMB ] 1Z9E [ RSDB ] PDB 2B4J [ SRS ] 2B4J [ PdbSum ], 2B4J [ IMB ] 2B4J [ RSDB ] HPRD O75475 Protein Interaction databases DIP O75475 IntAct O75475 Polymorphism : SNP, mutations, diseases OMIM 603620 [ map ] GENECLINICS 603620 SNP PSIP1 [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 436 SNP NM_021144 [SNP-NCI] SNP NM_033222 [SNP-NCI] SNP PSIP1 [GeneSNPs - Utah] PSIP1] [HGBASE - SRS] HAPMAP PSIP1 [HAPMAP] General knowledge Family PSIP1 [UCSC Family Browser] Browser SOURCE NM_021144 SOURCE NM_033222 SMD Hs.658434 SAGE Hs.658434 GO DNA binding [Amigo] DNA binding GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent PubGene PSIP1 Other databases Probes Probe PSIP1 Related clones (RZPD - Berlin) PubMed PubMed 39 Pubmed reference(s) in LocusLink Bibliography t(9;11)(p22;p15) in acute myeloid leukemia results in a fusion between NUP98 and the gene encoding transcriptional coactivators p52 and p75-lens epithelium-derived growth factor (LEDGF). Ahuja HG, Hong J, Aplan PD, Tcheurekdjian L, Forman SJ, Slovak ML. Cancer Res 2000; 60: 6227-6229. Medline 11103774

Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing. Singh DP, Kimura A, Chylack LT, Shinohara T. Gene 2000; 242: 265-273. Medline 10721720

Fusion of the NUP98 gene with the LEDGF/p52 gene defines a recurrent acute myeloid leukemia translocation. Hussey DJ, Moore S, Nicola M, Dobrovic A. BMC Genet 2001; 2:20. Medline 11737860

Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders. Wu X, Daniels T, Molinaro C, Lilly MB, Casiano CA Cell Death Differ 2002; 9: 915-925. Medline 12181742

HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 437 Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z. J Biol Chem 2003; 278: 372-381. Medline 12407101

Antinuclear autoantibodies in prostate cancer: immunity to LEDGF/p75, a survival protein highly expressed in prostate tumors and cleaved during apoptosis. Daniels T, Zhang J, Gutierrez I, Elliot ML, Yamada B, Heeb MJ, Sheets SM, Wu X, Casiano CA. Prostate 2005; 62: 14-26. Medline 15389814

NUP98-LEDGF fusion and t(9;11) in transformed chronic myeloid leukemia. Grand FH, Koduru P, Cross NC, Allen SL. Leuk Res 2005; 29: 1469-1472. Medline 15982735 t(9;11)(p22;p15) with NUP98-LEDGF fusion gene in pediatric acute myeloid leukemia. Morerio C, Acquila M, Rosanda C, Rapella A, Tassano E, Micalizzi C, Panarello C. Leuk Res 2005; 29: 467-470. Medline 15725483

DNA binding domains and nuclear localization signal of LEDGF: contribution of two helix-turn- helix (HTH)-like domains and a stretch of 58 amino acids of the N-terminal to the trans- activation potential of LEDGF. Singh DP, Kubo E, Takamura Y, Shinohara T, Kumar A, Chylack LT Jr, Fatma N. J Mol Biol 2006; 355: 379-394. Medline 16318853

Disruption of Ledgf/Psip1 results in perinatal mortality and homeotic skeletal transformations. Sutherland HG, Newton K, Brownstein DG, Holmes MC, Kress C, Semple CA, Bickmore WA. Mol Cell Biol 2006; 26: 7201-7210. Medline 16980622

Lens epithelium-derived growth factor is an Hsp70-2 regulated guardian of lysosomal stability in human cancer. Daugaard M, Kirkegaard-Sorensen T, Ostenfeld MS, Aaboe M, Hoyer-Hansen M, Orntoft TF, Rohde M, Jaattela M. Cancer Res 2007; 67: 2559-2567. Medline 17363574 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 03-2007 Cristina Morerio, Claudio Panarello Citation This paper should be referenced as such : Morerio C, Panarello C . PSIP1 (PC4 and SFRS1 interacting protein 1). Atlas Genet Cytogenet Oncol Haematol. March 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PSIP1ID405ch9q22.html

Atlas Genet Cytogenet Oncol Haematol 2007; 3 438

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 439 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MIRN21 (microRNA 21) Identity Other names hsa-mir-21 miR-21 Hugo MIRN21 Location 17q23.1 Based on Mapviewer, genes flanking MIRN21 oriented from centromere to telomere on 17q23 are: TMEM49, transmembrane protein 49, 17q23.1 . MIRN21, microRNA 21, 17q23.1 . Local_order TUBD1, tubulin, delta 1, 17q23.1 . LOC729565 ,similar to NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, 19kDa, 17q23.1 . RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1, 17q23.1 . DNA/RNA

A: Characterization of the full-length about 3433 nt pri-MIRN21. Open Reading frame analysis within the 3433 nucleotides identified a potential 124 amino acids long peptide. This uncharacterized ORF is located near the transcription start site (+114). This potential peptide sequence shows homology to a 180-amino-acid human protein. However, it is not clear yet if pri-MIRN21 functions as an mRNA as well. B: Stem-loop structure of MIRN21.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 440 Description The gene is located in an intergenic region. The length of MIRN21 gene is reported as 3433 nucleotides long. It overlaps with the 3' UTR end of the Transmembrane Protein 49 (TMEM 49) (also known as Human Vacuole Membrane Protein 1, VMP-1). Transcription RNA Pol II is suggested to be the most likely enzyme involved in miRNA transcription. However, current studies also provide evidences for RNA Pol III dependent transcription of few miRNAs interspersed among repetitive Alu elements. For MIRN21, the major RNA polymerase is likely to be RNA Pol II due to the presence of 5' cap and 3' poly (A) tail of the pri-MIRN21. Chromatin immunoprecipitation (ChIP) analysis of upstream sequences of MIRN21 showed enrichment for Pol II but not Pol III. MIRN21 gene was shown to harbor a 5' promoter element. 1008 bp DNA fragment for MIRN21 gene was cloned (-959 to +49 relative to T1 transcription site, see Figure 1; A). Analysis of the sequence showed a candidate "CCAAT" box transcription control element located approximately about 200 nt upstream of the T1 site. T1 transcription site was found to be located in a sequence similar to "TATA" box (ATAAACCAAGGCTCTTACCATAGCTG). To test the activity of the element, about 1kb DNA fragment was inserted into the 5' end of firefly luciferase indicator gene and transfected into 293T cells. The sense orientation insert, unlike antisense, induced luciferase activity. pri-MIRN21 gene was reported to have two transcription sites, T1 and T2. T1 (identified by RACE, +1 start site) was reported as the minor transcription site and T2 (identified by RACE, +27 start site) as the major transcription start site. Based on the data of pmiR-21-luc expression plasmid, the endogenous pri-MIRN21 was suggested to utilize T1 and T2 sites for initiation of transcription (Figure 1; A).

The maturation of miRNA gene involves sequential process.

Pri-miRNA The miRNA genes are first transcribed in nucleus as long primary transcripts called pri- miRNA. The primary transcript for MIRN21 is found to be 3433-nt long. For localization of the pri-MIRN21 transcript, total, nuclear and cytoplasmic RNA fractions from HeLa cells were oligo-dT primed and reverse transcribed into cDNA. pri- MIRN21 transcript was found mainly in the nucleus as well as modest levels in the cytoplasm. Sequence: NCBI cDNA clone: BC053563. Length: 3389bp

Pre-miRNA The primary transcripts of microRNAs are processed by enzymatic microprocessor Drosha (RNase III enzyme) and DGCR8 (dsRNA binding protein) from their 3' and 5' cleavage sites into an intermediate stem-loop precursor or pre-miRNA in the nucleus. The precursor of MIRN21 is 72 bases long (pre-MIRN21), forms a secondary structure, and contains the mature miRNA sequence, stem and terminal loop structures with 2-nt 3'overhang (Figure 1; B). The precursor is then transferred from nucleus to cytoplasm by the enzyme Exportin 5. In cytoplasm, a second RNase III enzyme, Dicer, removes terminal loop generating about 20-bp RNA duplex. Length: 72 bases Sequence: UGUCGGGUAGCUUAUCAGACUGAUGUUGACUGUUGAAUCUCAUGGCAACACCA GUCGAUGGGCUGUCUGACA (Figure 1; B).

Mature MIRN21 The mature miRNA forms one strand of the RNA duplex. One strand is degraded and other is incorporated in to a protein complex, RNA induced silencing complex (RISC), targeting a partially complementary target mRNA. MIRN21 is 22 nucleotides long. Sequence: UAGCUUAUCAGACUGAUGUUGA . Pseudogene No reported pseudogenes. Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 3 441 Note miRNAs are not translated into amino acids. Mutations Note In a panel of 91 human cancer cell lines representing several human cancers, sequencing showed no sequence variations in mature miRNAs. In HCT-15 colon cancer cell line, pri-MIRN21 showed a A+29G (A/G) heterozygous variation (Figure 2). It was suggested that sequence variations in pri-miRNAs may cause structural alterations. However, the variation was not found to be affecting pri-MIRN21 processing when it was compared to the wild type.

Localization of sequence variation in pri-MIRN21 in HTC-15 colon cancer cell line.

Implicated in Entity Human neoplasms. Note Overexpression was fist shown in glioblastoma and then in papillary thyroid carcinoma (PTC), breast tumors and other various tumors (e.g. colorectal carcinoma, lung tumors, pancreatic tumors, prostate tumors, stomach tumors cholangiocarcinomas, neuroblastoma, hepatocellular carcinoma and uterine leiomyomas) and cervical adenocarcinoma cell line, HeLa. Relatively low expression was seen in cell lines HL-60 (promyelocytic leukemia), K562 (chronic myelogenous leukemia) and prostatic adenocarcinoma cell line. miRNA microarray data from 540 samples from 6 solid cancers (lung, stomach, prostate, colon, pancreatic and breast) showed overexpression of MIRN21 gene compared to normal cells.

Entity Glioblastoma Disease Overexpression of MIRN21 was first shown in malignant human brain tumor cells. When, human glioblastoma tumor tissues, 12 early passage cultures (passage 3) from high grade gliomas and 6 glioblastoma cell lines (A172, U87, U373, LN229, LN428 and LN308) were compared to non-neoplastic glial cells and a variety of mammalian tissues, MIRN21 was found to be strongly overexpressed in the neoplastic samples. Moreover, oligonucleotide microarrays specific for 180 human and mouse miRNAs and Northern blotting methods were used to profile expression of MIRN21.In glioblastoma tissues its expression showed 5 to 100 fold increase compared to non- neoplastic brain sample and 5 to 30 fold increase in cell lines compared to normal. Oncogenesis Apoptosis: Loss-of-function approach was used to identify the biological significance of MIRN21 in glioblastoma cells. Sequence specific inhibitors (2¹-O-methyl- oligonucleotides) were used to knock-down MIRN21 transcript and apoptosis activity (caspase-3 and caspase-7 enzymatic activities) was measured. 48 hours post- transfection, caspase activity increased 3-folds suggesting that MIRN21 acted as an anti-apoptotic factor in glioblastoma cells through blocking expression of key apoptosis-enabling genes.

Entity Breast Cancer. Disease from 76 breast cancer tumors and 14 cell lines were analyzed by using miRNA

Atlas Genet Cytogenet Oncol Haematol 2007; 3 442 microarray and Northern blotting (10 normal samples were used for comparison and normalization). MIRN21 was up-regulated and the results were confirmed by Northern blotting. Consistent with other studies, MIRN21 overexpression in breast tumors compared to matched normal breast tissues was verified by stem-loop RT real-time PCR and miRNA microarrays containing 157 mature human miRNAs. Oncogenesis Apoptosis: Inhibition of MIRN21 in breast cancer cell line MCF-7 by transfection of anti-mir-21 inhibitors (chemically modified oligonucleotides) showed growth inhibition. Treatment of transfected MCF-7 cell line with anticancer drug topotecan (TPT) caused cell growth inhibition by 40%. The results suggested suppression of MIRN21 gene could sensitize tumor cells to anticancer drugs. Inhibition of MIRN21 in a xenograft carcinoma mouse model verified tumor growth suppression. Transfection results of MCF-7 cells with a general caspase inhibitor suggested MIRN21 role in regulation of bcl-2 gene expression indirectly, possibly controlling expression of genes involved in apoptosis pathways including bcl-2.

Entity Pancreatic cancer. Disease 16 pancreatic adenocarcinomas and 10 adjacent benign tissues compared to 6 normal pancreas samples were analyzed for MIRN21 precursor expression and compared to mature MIRN21 by using real-time PCR assay. The results were consistent between precursor and mature MIRN21 showing overexpression.

Entity Neuroblastoma. Disease Neuroblastoma cell line, SH-SY5Y, was treated with a tumor promoting agent (12-O- tetradecanoyl phorbol 13-acetate (TPA)) to induce differentiation into a neuronal phenotype. Following stimulation, microarray analysis of stem-loop precursors was performed and MIRN21 showed 7-8 times higher expression compared to other up- regulated miRNAs showing 2-4 times relative increase.

Entity Lung cancer. Disease Analysis of 104 pairs of primary lung cancers and non-cancerous lung tissues by microRNA microarray showed differential expression of mature MIRN21 among phenotypical and histological classifications. The results were confirmed by solution hybridization and RT-PCR. The results verified up-regulation of MIRN21 in lung cancer tissues compared to normals. Moreover, real time RT-PCR results for stem-loop precursor of MIRN21 showed at least 2-fold up-regulation in 66% of 32 cases.

Entity Other cancers. Disease In other miRNA microarray studies, MIRN21 was found to be overexpressed in papillary thyroid cancer, hepatocellular carcinoma, cholangiocarcinomas and uterine leiomyomas. A study suggested that MIRN21 inhibition in a cervical adenocarcinoma cell line, HeLa, caused increase in cell growth. Prognosis MIRN21 (as well as 7 other miRNAs) expresion was correlated with adenocarcinoma patients¹ survival. Patients that have high expression of MIRN21 were found to have worse prognosis. Thus, in addition to potential role of MIRN21 in lung carcinogenesis through apoptosis pathway, it was suggested that expression profiles could be informative in adenocarcinoma patient survival. Cytogenetics Genomic amplification of chromosome band 17q23.2 in neuroblastoma, breast cancer, colon cancer, lung cancer is known. Oncogenesis Apoptosis: MIRN21 was found to be highly over-expressed in malignant cholangiocytes. In cholangiocarcinoma cells it was shown that one of the targets of MIRN21 was PTEN encoding phosphatase that inhibited the survival and growth promoting activity of PI 3-kinase (phosphoinositole 3-kinase) signaling. In another report, inhibiton of MIRN21 showed increased sensitivity to gemcitabine.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 443 The results suggested that MIRN21 regulated gemcitabine-induced apoptosis by PTEN (phosphatase and tensin homolog) dependent activation of PI 3-kinase and AKT/mTOR signaling. These studies suggested anti-apoptotic role for the MIRN21 gene.

External links Nomenclature Hugo MIRN21 GDB MIRN21 Entrez_Gene MIRN21 406991 microRNA 21 Cards Atlas MIRN21ID44019ch17q23 GeneCards MIRN21 Ensembl MIRN21 Genatlas MIRN21 GeneLynx MIRN21 eGenome MIRN21 euGene 406991 Genomic and cartography GoldenPath MIRN21 - 17q23.1 Ensembl MIRN21 - [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene MIRN21 Gene and transcription Genbank AF480524 [ ENTREZ ] Genbank AJ421741 [ ENTREZ ] Genbank AY699265 [ ENTREZ ] Genbank BC053563 [ ENTREZ ] RefSeq NT_010783 [ SRS ] NT_010783 [ ENTREZ ] AceView MIRN21 AceView - NCBI Unigene Hs.444569 [ SRS ] Hs.444569 [ NCBI ] HS444569 [ spliceNest ] Protein : pattern, domain, 3D structure Protein Interaction databases Polymorphism : SNP, mutations, diseases OMIM 611020 [ map ] GENECLINICS 611020 SNP MIRN21 [dbSNP-NCBI] SNP MIRN21 [GeneSNPs - Utah] MIRN21] [HGBASE - SRS] HAPMAP MIRN21 [HAPMAP] General knowledge Family MIRN21 [UCSC Family Browser] Browser SMD Hs.444569

Atlas Genet Cytogenet Oncol Haematol 2007; 3 444 SAGE Hs.444569 PubGene MIRN21 Other databases Probes Probe MIRN21 Related clones (RZPD - Berlin) PubMed PubMed 7 Pubmed reference(s) in LocusLink Bibliography The nuclear Rnase III Drosha initiates microRNA processing. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN. Nature. 2003; 425: 415-418. Medline 14508493

Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. Cai X, Hagedorn CH, Cullen BR. RNA. 2004; 10 :1957-1966. Medline 15525708

Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM. PNAS. 2004; 101: 2999-3004. Medline 14973191

Human embryonic stem cells express a unique set of microRNAs. Suh MR, Lee Y, Kim JY, Kim SK, Moon SH, Lee JY, Cha KY, Chung HM, Yoon HS, Moon SY, Kim VN, Kim KS. Dev Biol. 2004; 270: 488-498. Medline 15183728

MicroRNA-21 Is an Antiapoptotic Factor in Human Glioblastoma Cells. Chan JA, Krichevsky AM, Kosik KS. Cancer Res. 2005; 65: (14). Medline 16024602

Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Cheng AM, Byrom MW, Shelton J, Ford LP. Nucleic Acids Res. 2005; 4:1290-1297. Medline 15741182

Exploration of human miRNA target genes in neuronal differentiation. Fukuda Y, Kawasaki H, Taira K. Nucleic Acids Symp Ser (Oxf). 2005; 49: 341-342. Medline 17150773

The role of microRNA genes in papillary thyroid carcinoma. He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, Calin GA, Liu CG, Franssila K, Suster S, Kloos RT, Croce CM, de la Chapelle A. PNAS. 2005; 102: 19075-19080.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 445 Medline 16365291

MicroRNA Gene Expression Deregulation in Human Breast Cancer. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM. Cancer Res. 2005; 65: 7065-7070. Medline 16103053

Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. Zeng Y, Yi R, Cullen BR. The EMBO Journal. 2005; 24: 138-148. Medline 15565168

RNA polymerase III transcribes human microRNAs. Borchert GM, Lanier W, Davidson BL. Nat Struct Mol Biol. 2006; 12: 1097-1101. Medline 17099701

MicroRNAs and chromosomal abnormalities in cancer cells. Calin GA, Croce CM. Oncogene. 2006; 25: 6202-6210 (REVIEW). Medline 17028600

Sequence variations of microRNAs in human cancer: alterations in predicted secondary structure do not affect processing. Diederichs S, Haber DA. Cancer Res. 2006; 66:6097-6104. Medline 16778182 miR-21-mediated tumor growth. Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. Oncogene. 2006; 1-5. Medline 17072344

A microRNA expression signature of human solid tumors defines cancer gene targets. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM. PNAS. 2006; 103: 2257-2261. Medline 16461460

Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC. Cancer Cell. 2006; 9:189-198. Medline 16530703

Expression profiling identifies microRNA signature in pancreatic cancer. Lee EJ, Gusev Y, Jiang J, Nuovo GJ, Lerner MR, Frankel WL, Morgan DL, Postier RG, Brackett DJ, Schmittgen TD. Int J Cancer. 2007; 120:1046-1054. Medline 17149698

Atlas Genet Cytogenet Oncol Haematol 2007; 3 446 A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas. Wang T, Zhang X, Obijuru L, Laser J, Aris V, Lee P, Mittal K, Soteropoulos P, Wei JJ. Genes Chromosomes Cancer. 2007; 46: 336-347. Medline 17243163

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 03-2007 Sadan Duygu Selcuklu, Mustafa Cengiz Yakicier, Ayse Elif Erson Citation This paper should be referenced as such : Selcuklu SD, Yakicier MC, Erson AE . MIRN21 (microRNA 21). Atlas Genet Cytogenet Oncol Haematol. March 2007 . URL : http://AtlasGeneticsOncology.org/Genes/MIRN21ID44019ch17q23.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 447 Atlas of Genetics and Cytogenetics in Oncology and Haematology

KLF6 (Krüppel like factor 6) Identity Other names BCD1 COPEB (Core promoter binding protein) CPBP GBF PAC1 ST12 Zf9 Hugo KLF6 Location 10p15.1 DNA/RNA Description Spans 11 kb; five exons; 4 CDS exons. Transcription Full length transcript of 4.1 kb, open reading frame 849 bp. There are at least three alternative splice transcripts. Protein Description Full length transcript encodes a 283 amino acids protein, 42 kDa, with a 201 amino acids transactivation domain and an 82 amino acids DNA binding domain with 3 C2H2 zinc fingers. There is at least one putative nuclear localization signal immediately 5' to the DNA binding domain. There are at least three alternative splice transcripts encoding proteins of 195 (KLF6- SV1), 237 (KLF6-SV3), and 241 amino acids (KLF6-SV2). Several post-translational modifications including phosphorylation, ubiquitinylation, acetylation are suggested based on encoded protein sequence motifs. Expression Ubiquitously expressed in adult tissues, restricted during embryogenesis but includes placenta, neural and non-neural tissues, and cornea. Full-length KLF6 downregulated in many human cancers (see below). Expression pattern of KLF6 splice variants may be upregulated. Localisation Found in both nucleus and cytoplasm, but predominantly nuclear. Splice variants SV1 and SV2 primarily cytoplasmic and believed to be the result of loss of nuclear localization signal (NLS). Splice variant 3 retains the NLS. Function Tumor suppressor gene, immediate early gene in tissue injury and fibrosis, during adenoviral and pseudomonas infections and during ischemic reperfusion in kidney. Transactivator of multiple target genes including p21, TGFbeta1, TGFbeta receptors type II and TGFbeta receptors type III, human keratin 4 and 12 genes: inducible nitric oxide synthase, endoglin, insulin-like growth factor receptor 1, multi-drug resistance transporters, E-cadherin, leukotriene C(4)(LTC4S), 111, acid ceramidase, alpha 1 proteinase inhibitor. Suppresses growth by inducing p21, sequestering cyclin D1 and/or inhibiting c-jun oncogene. Promotes differentiation of preadipocytes to adipocytes in culture and hepatocytes in vivo. Contributes to fetal development of mouse cornea and lens; and immune and hematopoietic systems by contributing to hemangioblast phenotype. Interacts with the core promoter element of a TATA box-less gene. Induces apoptosis of lung cancer cells.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 448 Homology The 47 N-terminal amino acids are identical to KLF7, and the 82 amino acids DNA binding domain highly homologous to other members of the KLF family. Also homologous to the Drosophila Luna gene. Mutations Germinal None identified to date. However, a germline single nucleotide intronic polymorphism (IVS1-27 G > A) has been identified that creates a novel SRp40 DNA binding site, therby increasing the generation of three alternatively spliced mRNAs, and which is associated with an increased risk of prostate cancer. Other low frequency coding and non-coding SNPs have been identified. Somatic A number of somatic mutations were originally identified in prostate cancer and shown to result in loss of function. These include Trp64Arg, Ser116Pro, Ala123Asp and Ser137X. External links Nomenclature Hugo KLF6 GDB KLF6 Entrez_Gene KLF6 1316 Kruppel-like factor 6 Cards Atlas KLF6ID44002ch10p15 GeneCards KLF6 Ensembl KLF6 Genatlas KLF6 GeneLynx KLF6 eGenome KLF6 euGene 1316 Genomic and cartography GoldenPath KLF6 - 10p15.1 chr10:3808189-3817455 - 10p15 (hg18-Mar_2006) Ensembl KLF6 - 10p15 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene KLF6 Gene and transcription Genbank AB017493 [ ENTREZ ] Genbank AF001461 [ ENTREZ ] Genbank AI355637 [ ENTREZ ] Genbank BC000311 [ ENTREZ ] Genbank BC004301 [ ENTREZ ] RefSeq NM_001008490 [ SRS ] NM_001008490 [ ENTREZ ] RefSeq NM_001300 [ SRS ] NM_001300 [ ENTREZ ] RefSeq AC_000053 [ SRS ] AC_000053 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_077567 [ SRS ] NT_077567 [ ENTREZ ] RefSeq NW_924584 [ SRS ] NW_924584 [ ENTREZ ] AceView KLF6 AceView - NCBI Unigene Hs.4055 [ SRS ] Hs.4055 [ NCBI ] HS4055 [ spliceNest ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 449 Protein : pattern, domain, 3D structure SwissProt O43838 [ SRS] O43838 [ EXPASY ] O43838 [ INTERPRO ] CluSTr O43838 Blocks O43838 HPRD O43838 Protein Interaction databases DIP O43838 IntAct O43838 Polymorphism : SNP, mutations, diseases OMIM 137215;176807;602053 [ map ] GENECLINICS 137215;176807;602053 SNP KLF6 [dbSNP-NCBI] SNP NM_001008490 [SNP-NCI] SNP NM_001300 [SNP-NCI] SNP KLF6 [GeneSNPs - Utah] KLF6] [HGBASE - SRS] HAPMAP KLF6 [HAPMAP] General knowledge Family KLF6 [UCSC Family Browser] Browser SOURCE NM_001008490 SOURCE NM_001300 SMD Hs.4055 SAGE Hs.4055 GO molecular_function [Amigo] molecular_function GO nucleic acid binding [Amigo] nucleic acid binding GO DNA binding [Amigo] DNA binding GO cellular_component [Amigo] cellular_component GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO biological_process [Amigo] biological_process GO zinc ion binding [Amigo] zinc ion binding GO cell growth [Amigo] cell growth GO transcriptional activator activity [Amigo] transcriptional activator activity GO B cell differentiation [Amigo] B cell differentiation GO metal ion binding [Amigo] metal ion binding PubGene KLF6 Other databases Probes Probe KLF6 Related clones (RZPD - Berlin) PubMed PubMed 43 Pubmed reference(s) in LocusLink

Atlas Genet Cytogenet Oncol Haematol 2007; 3 450 Bibliography Transcriptional activation of transforming growth factor beta1 and its receptors by the Kruppel- like factor Zf9/core promoter-binding protein and Sp1. Potential mechanisms for autocrine fibrogenesis in response to injury. Kim Y, Ratziu V, Choi SG, Lalazar A, Theiss G, Dang Q, Kim SJ, Friedman SL. J Biol Chem. 1998; 273(50): 33750-33758. Medline 9837963

Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis. Ratziu V, Lalazar A, Wong L, Dang Q, Collins C, Shaulian E, Jensen S, Friedman SL. Proc Natl Acad Sci U S A. 1998; 95(16): 9500-9505. Medline 9689109

Transcriptional activation of urokinase by the Kruppel-like factor Zf9/COPEB activates latent TGF-beta1 in vascular endothelial cells. Kojima S, Hayashi S, Shimokado K, Suzuki Y, Shimada J, Crippa MP, Friedman SL. Blood. 2000; 95(4): 1309-1316. Medline 10666204

Kruppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact. Okano J, Opitz OG, Nakagawa H, Jenkins TD, Friedman SL, Rustgi AK. FEBS Lett. 2000; 473(1): 95-100. Medline 10802067

Cell-specific transcription of leukotriene C(4) synthase involves a Kruppel-like transcription factor and Sp1. Zhao JL, Austen KF, Lam BK. J Biol Chem. 2000; 275(12): 8903-8910. Medline 10722737

Co-localization of KLF6 and KLF4 with pregnancy-specific glycoproteins during human placenta development. Blanchon L, Bocco JL, Gallot D, Gachon AM, Lemery D, Dechelotte P, Dastugue B, Sapin V. Mech Dev. 2001; 105(1-2): 185-189. Medline 11429296

Klf6 is a zinc finger protein expressed in a cell-specific manner during kidney development. Fischer EA, Verpont MC, Garrett-Sinha LA, Ronco PM, Rossert JA. J Am Soc Nephrol. 2001; 12(4): 726-735. Medline 11274234

Embryonic expression of Kruppel-like factor 6 in neural and non-neural tissues. Laub F, Aldabe R, Ramirez F, Friedman S. Mech Dev. 2001; 106(1-2): 167-170. Medline 11472850

KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Narla G, Heath KE, Reeves HL, Li D, Giono LE, Kimmelman AC, Glucksman MJ, Narla J, Eng FJ, Chan AM, Ferrari AC, Martignetti JA, Friedman SL. Science. 2001; 294(5551): 2563-2566. Medline 11752579

Transcriptional activation of endoglin and transforming growth factor-beta signaling

Atlas Genet Cytogenet Oncol Haematol 2007; 3 451 components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Botella LM, Sanchez-Elsner T, Sanz-Rodriguez F, Kojima S, Shimada J, Guerrero-Esteo M, Cooreman MP, Ratziu V, Langa C, Vary CP, Ramirez JR, Friedman S, Bernabeu C. Blood. 2002; 100(12): 4001-4010. Medline 12433697

Regulation of corneal keratin-12 gene expression by the human Kruppel-like transcription factor 6. Chiambaretta F, Blanchon L, Rabier B, Kao WW, Liu JJ, Dastugue B, Rigal D, Sapin V. Invest Ophthalmol Vis Sci. 2002; 43(11): 3422-3429. Medline 12407152

The Kruppel-like factor Zf9 and proteins in the Sp1 family regulate the expression of HSP47, a collagen-specific molecular chaperone. Yasuda K, Hirayoshi K, Hirata H, Kubota H, Hosokawa N, Nagata K. J Biol Chem. 2002; 277(47): 44613-44622. Medline 12235161

Deletion, mutation, and loss of expression of KLF6 in human prostate cancer. Chen C, Hyytinen ER, Sun X, Helin HJ, Koivisto PA, Frierson HF Jr, Vessella RL, Dong JT. Am J Pathol. 2003; 162(4): 1349-1354. Medline 12651626

Identification of the Drosophila progenitor of mammalian Kruppel-like factors 6 and 7 and a determinant of fly development. De Graeve F, Smaldone S, Laub F, Mlodzik M, Bhat M, Ramirez F. Gene. 2003; 314: 55-62. Medline 14527717

KLF6, a putative tumor suppressor gene, is mutated in astrocytic gliomas. Jeng YM, Hsu HC. Int J Cancer. 2003; 105(5): 625-629. Medline 12740910

Transcriptional activation of the human inducible nitric-oxide synthase promoter by Kruppel- like factor 6. Warke VG, Nambiar MP, Krishnan S, Tenbrock K, Geller DA, Koritschoner NP, Atkins JL, Farber DL, Tsokos GC. J Biol Chem. 2003; 278(17): 14812-14819. Medline 12590140

Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1. Benzeno S, Narla G, Allina J, Cheng GZ, Reeves HL, Banck MS, Odin JA, Diehl JA, Germain D, Friedman SL. Cancer Res. 2004; 64(11): 3885-3891. Medline 15172998

Kruppel-like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells. Ito G, Uchiyama M, Kondo M, Mori S, Usami N, Maeda O, Kawabe T, Hasegawa Y, Shimokata K, Sekido Y. Cancer Res. 2004; 64(11): 3838-3843. Medline 15172991

Atlas Genet Cytogenet Oncol Haematol 2007; 3 452

Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6. Kimmelman AC, Qiao RF, Narla G, Banno A, Lau N, Bos PD, Nunez Rodriguez N, Liang BC, Guha A, Martignetti JA, Friedman SL, Chan AM. Oncogene. 2004; 23(29): 5077-5083. Medline 15064720

Frequent inactivation of the tumor suppressor Kruppel-like factor 6 (KLF6) in hepatocellular carcinoma. Kremer-Tal S, Reeves HL, Narla G, Thung SN, Schwartz M, Difeo A, Katz A, Bruix J, Bioulac-Sage P, Martignetti JA, Friedman SL. Hepatology. 2004; 40(5): 1047-1052. Medline 15486921

Developmentally regulated expression of KLF6 in the mouse cornea and lens. Nakamura H, Chiambaretta F, Sugar J, Sapin V, Yue BY. Invest Ophthalmol Vis Sci. 2004; 45(12): 4327-4332. Medline 15557439

Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer. Reeves HL, Narla G, Ogunbiyi O, Haq AI, Katz A, Benzeno S, Hod E, Harpaz N, Goldberg S, Tal- Kremer S, Eng FJ, Arthur MJ, Martignetti JA, Friedman SL. Gastroenterology. 2004; 126(4): 1090-1103. Medline 15057748

Transcriptional activation of the insulin-like growth factor I receptor gene by the Kruppel-like factor 6 (KLF6) tumor suppressor protein: potential interactions between KLF6 and p53. Rubinstein M, Idelman G, Plymate SR, Narla G, Friedman SL, Werner H. Endocrinology. 2004; 145(8): 3769-3777. Medline 15131018

A new role for the Kruppel-like transcription factor KLF6 as an inhibitor of c-Jun proto- oncoprotein function. Slavin DA, Koritschoner NP, Prieto CC, Lopez-Diaz FJ, Chatton B, Bocco JL. Oncogene. 2004; 23(50): 8196-8205. Medline 15378003

Genetic alterations of the KLF6 gene in gastric cancer. Cho YG, Kim CJ, Park CH, Yang YM, Kim SY, Nam SW, Lee SH, Yoo NJ, Lee JY, Park WS. Oncogene. 2005; 24(28): 4588-4590. Medline 15824733

Genomic organization and functional analysis of the gene encoding the Kruppel-like transcription factor KLF6. Gehrau RC, D'Astolfo DS, Prieto C, Bocco JL, Koritschoner NP. Biochim Biophys Acta. 2005; 1730(2): 137-146. Medline 16054710

Regulation of Kruppel-like factor 6 tumor suppressor activity by acetylation. Li D, Yea S, Dolios G, Martignetti JA, Narla G, Wang R, Walsh MJ, Friedman SL. Cancer Res. 2005; 65(20): 9216-9225. Medline 16230382

Atlas Genet Cytogenet Oncol Haematol 2007; 3 453 Kruppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3- dependent repression of DLK1. Li D, Yea S, Li S, Chen Z, Narla G, Banck M, Laborda J, Tan S, Friedman JM, Friedman SL, Walsh MJ. J Biol Chem. 2005; 280(29): 26941-26952. Medline 15917248

A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Narla G, Difeo A, Reeves HL, Schaid DJ, Hirshfeld J, Hod E, Katz A, Isaacs WB, Hebbring S, Komiya A, McDonnell SK, Wiley KE, Jacobsen SJ, Isaacs SD, Walsh PC, Zheng SL, Chang BL, Friedrichsen DM, Stanford JL, Ostrander EA, Chinnaiyan AM, Rubin MA, Xu J, Thibodeau SN, Friedman SL, Martignetti JA. Cancer Res. 2005; 65(4): 1213-1222. Medline 15735005

Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread. Narla G, DiFeo A, Yao S, Banno A, Hod E, Reeves HL, Qiao RF, Camacho-Vanegas O, Levine A, Kirschenbaum A, Chan AM, Friedman SL, Martignetti JA. Cancer Res. 2005; 65(13): 5761-5768. Medline 15994951

E-cadherin is a novel transcriptional target of the KLF6 tumor suppressor. DiFeo A, Narla G, Camacho-Vanegas O, Nishio H, Rose SL, Buller RE, Friedman SL, Walsh MJ, Martignetti JA. Oncogene. 2006; 25(44): 6026-6031. Medline 16702959

Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination. DiFeo A, Narla G, Hirshfeld J, Camacho-Vanegas O, Narla J, Rose SL, Kalir T, Yao S, Levine A, Birrer MJ, Bonome T, Friedman SL, Buller RE, Martignetti JA. Clin Cancer Res. 2006; 12(12): 3730-3739. Medline 16778100

Developmental regulation of yolk sac hematopoiesis by Kruppel-like factor 6. Matsumoto N, Kubo A, Liu H, Akita K, Laub F, Ramirez F, Keller G, Friedman SL. Blood. 2006; 107(4): 1357-1365. Medline 16234353

Genome-wide single nucleotide polymorphism analysis of lung cancer risk detects the KLF6 gene. Spinola M, Leoni VP, Galvan A, Korsching E, Conti B, Pastorino U, Ravagnani F, Columbano A, Skaug V, Haugen A, Dragani TA. Cancer Lett, 2007. Medline 17223258

KLF6: mutational analysis and effect on cancer cell proliferation. Yin D, Komatsu N, Miller CW, Chumakov AM, Marschesky A, McKenna R, Black KL, Koeffler HP. Int J Oncol. 2007; 30(1): 65-72. Medline 17143513

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

Atlas Genet Cytogenet Oncol Haematol 2007; 3 454 BiblioGene - INIST Search in all EBI

Contributor(s) Written 03-2007 Scott L. Friedman, Goutham Narla, John A. Martignetti Citation This paper should be referenced as such : Friedman SL, Narla G, Martignetti JA . KLF6 (Krüppel like factor 6). Atlas Genet Cytogenet Oncol Haematol. March 2007 . URL : http://AtlasGeneticsOncology.org/Genes/KLF6ID44002ch10p15.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 455 Atlas of Genetics and Cytogenetics in Oncology and Haematology

IL6 (interleukin 6 (interferon beta 2)) Identity Other names interleukin 6 interferon beta 2 IL-6 HSF HGF CDF BSF2 IFNB2 Hugo IL6 Location 7p15.3 Local_order cen. - - LOC221838 - IL6 - TOMM7 - DRCTNNB1A - tel. IMAGE DNA/RNA

The gene for IL6 is shown in light blue and comprizes 6 exons (with 375 bp, 103 bp, 191 bp, 114 bp, 147 bp and 542 bp in length) and 5 introns (with 920 bp, 162 bp, 1058 bp, 707 bp and 1745 bp in length). The coding part is shown in dark blue.

Description 6 exons. Transcriptio 1472 bp transcript with a 639 bp of coding sequence. n Protein

The IL6 protein (shown in light green) shares C-terminal a homologous region (shown in dark green) also found in IL23A and CSF3.

Description 212 amino acids, 23.7 kd, containing 4 alpha-helices.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 456 Homology IL6 shares sequence homology with IL23 (IL23A) and G-CSF (CSF3). Mutations Note G/C polymorphism at nucleotide -174 (promoter region) Breast cancer prognosis differs between populations. Despite its lower incidence in Blacks when compared to Caucasians, mortality among the former is higher. Genetic factors involved in the molecular pathways regulating tumor development have been adduced to explain these differences, and it has been suggested that the IL-6 gene is a susceptibility factor underlying ethnic differences in breast cancer survival. Reports of a G/C polymorphism at nucleotide -174 within the promoter region of the IL-6 gene support this contention. This polymorphism modulates IL-6 expression and allele/genotype frequencies at the -174 site differ significantly between ethnic groups. Implicated in Entity Various cancers Note Although IL6 necessary to support growth of multiple myeloma cells, and is upregulated in certain tumor types, notably lung (squamous), bladder and prostate carcinomas, no recurrent chromosome rearrangements at 7p21 or IL6 rearrangements have been observed in these neoplasms.

Entity Breast cancer Cytogenetics No rearrangements reported. Oncogenesis Some cytokines, including IL-6, stimulate breast cancer proliferation or invasion and serve as negative prognostic indicators. Hitherto IL-2, IFNalpha, IFNbeta IFNgamma, IL-6, IL-12 have been used for anti tumour treatment of advanced breast cancer either to induce or increase hormone sensitivity and/or to stimulate cellular immunity. Cytokines, such as IL-6 play a key role in regulating estrogen synthesis in normal and malignant breast tissues. The activities of estradiol 17beta-hydroxysteroid dehydrogenase and estrone sulfatase are all increased by IL-6. Prostaglandin E2 may also be an important regulator of estradiol activity in breast tumors while invading macrophages and lymphocytes may also stimulate estrogen synthesis in breast cancers.

Entity Multiple myeloma Cytogenetics No rearrangements reported. Oncogenesis Although interleukin-6 (IL-6) is considered as a key growth factor for myeloma cells, only a few subpopulations of tumor cells, such as CD45(+) immature cells, proliferate in response to IL-6. However, increasing numbers of cytokines, chemokines and cell- to-cell contacts been support growth of MM cells. It has repeatedly shown that oncogenic mutations as well as the bone marrow matrix (BMM) stimulate IL-6- independent signalling pathways that protect MM cells from apoptosis.Hyperdiploid MM tumors contain multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15 , 19 , and 21, but rarely have IgH translocations, although CCND-1/CCND-2/CCND-3 dysregulation appears to occur as an early event. This may sensitize these cells to proliferative stimuli, resulting in selective expansion as a result of interaction with BMM that produce IL-6 and other cytokines. Three types of growth factors have been identified in plasma cells: - The IL-6 family cytokines, which activate the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein (MAP) kinase pathways; - Growth factors activating the phosphatidylinositol (PI)-3 kinase/AKT and MAP kinase pathways, and - B-cell-activating factor (BAFF) or proliferation-inducing ligand (APRIL). These growth factors may operate synergetically being co-localized together with cytoplasmic transduction elements in membrane caveolae. Proteasome inhibitors are emerging as a promising class of anti-cancer therapeutic

Atlas Genet Cytogenet Oncol Haematol 2007; 3 457 agents in MM, e.g. bortezomib which inhibits NF-kappaB translocation / transcription and critical signalling pathways, notably IL-6-induced proliferation and/or survival.

Entity Prostate cancer Cytogenetics No rearrangements reported. Oncogenesis IL-6 induces divergent proliferative responses in prostate cells. IL-6 is expressed in benign and malignant prostate tissue and levels of both IL-6 and IL-6R increase during prostate carcinogenesis. Serum levels of IL-6 are elevated in patients with treatment- refractory prostate carcinoma.IL-6 has also been shown to promote prostate cell growth, except in LNCaP cells, in which arrest and differentiation are produced. IL-6 induces activation of the (AR) in the absence of androgen. IL-6 also modulates vascular endothelial growth factor expression and neuroendocrine differentiation in prostate cells. Anti-IL-6 antibodies showed an inhibitory effect on PC- 3 xenografts. Hence, IL-6 is widely considered a promising potential therapeutic target in prostate cancer. Androgen receptor (AR), which is generally expressed in prostate cancers, promotes tumor progression in various ways, including ligand-independent activation. IL-6 is among the most important nonsteroidal regulators of AR activity reaching about half the maximum levels achieved by AR alone. At low concentrations of androgen, IL-6 and androgen operate synergistically to activate AR. In prostate carcinoma cells homeodomain protein GBX2 was identified to contribute directly to IL6 expression by binding within the promoter region containing the consensus sequence for GBX2.

Entity Hodgkin lymphoma Cytogenetics No rearrangements detected. Oncogenesis Hodgkin lymphoma (HL) cells express multiple cytokines, notably IL6, which contributes to the immunoreactive phenotype and of which high levels are associated with bad prognosis. Both transcription factors, NFkB and AP1 are constitutively activated in in HL cells driving expression of IL6 and also disturbing the pro/anti- apoptotic balance. Additionally, homeodomain protein HLXB9 contributes to the IL6 expression. HLXB9 is closely related to homeodomain protein GBX2 contributing to IL6 expression in prostate carcinoma cells. So, tumor type specific homeobox genes are involved in high level expression of IL6.

Entity Cancer cachexia Cytogenetics No rearrangements reported. Oncogenesis Unlike acute inflammation which is a defense response, chronic inflammation may promote cancer. Several pro-inflammatory gene products modulate apoptosis, proliferation, angiogenesis, invasion, and metastasis, including IL-6, which is subject to regulation by NF-kB, which is constitutively active in most tumors. About one-in-three cancer deaths are due to cachexia (wasting) following the hypercatabolism of the body's carbon sources. Tumor-inflammatory responses encompass synthesis of cytokines, including IL-6 which induces cachexia by altering lipids and protein metabolism. IL-6-like cytokines inhibit lipid biosynthesis by adipocytes and cause the atrophy and increased catabolism of muscle protein. Reduced serum IL-6 levels induced by medroxyprogesterone acetate has been reported to exert an anti-cachectic effect in advanced breast cancer.

External links Nomenclature Hugo IL6 GDB IL6

Atlas Genet Cytogenet Oncol Haematol 2007; 3 458 Entrez_Gene IL6 3569 interleukin 6 (interferon, beta 2) Cards Atlas IL6ID519ch7p15 GeneCards IL6 Ensembl IL6 Genatlas IL6 GeneLynx IL6 eGenome IL6 euGene 3569 Genomic and cartography GoldenPath IL6 - 7p15.3 chr7:22733345-22738141 + 7p21 (hg18-Mar_2006) Ensembl IL6 - 7p21 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene IL6 Gene and transcription Genbank A09363 [ ENTREZ ] Genbank BC015511 [ ENTREZ ] Genbank BT019748 [ ENTREZ ] Genbank BT019749 [ ENTREZ ] Genbank CR450296 [ ENTREZ ] RefSeq NM_000600 [ SRS ] NM_000600 [ ENTREZ ] RefSeq AC_000050 [ SRS ] AC_000050 [ ENTREZ ] RefSeq AC_000068 [ SRS ] AC_000068 [ ENTREZ ] RefSeq NC_000007 [ SRS ] NC_000007 [ ENTREZ ] RefSeq NT_007819 [ SRS ] NT_007819 [ ENTREZ ] RefSeq NT_079592 [ SRS ] NT_079592 [ ENTREZ ] RefSeq NW_923240 [ SRS ] NW_923240 [ ENTREZ ] AceView IL6 AceView - NCBI Unigene Hs.654458 [ SRS ] Hs.654458 [ NCBI ] HS654458 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P05231 [ SRS] P05231 [ EXPASY ] P05231 [ INTERPRO ] Prosite PS00254 INTERLEUKIN_6 [ SRS ] PS00254 INTERLEUKIN_6 [ Expasy ] Interpro IPR009079 4_helix_cytokine [ SRS ] IPR009079 4_helix_cytokine [ EBI ] Interpro IPR012351 Cytokine_4_hlx [ SRS ] IPR012351 Cytokine_4_hlx [ EBI ] Interpro IPR003573 IL6_MGF_GCSF [ SRS ] IPR003573 IL6_MGF_GCSF [ EBI ] Interpro IPR003574 Interleukin_6 [ SRS ] IPR003574 Interleukin_6 [ EBI ] CluSTr P05231 Pfam PF00489 IL6 [ SRS ] PF00489 IL6 [ Sanger ] pfam00489 [ NCBI-CDD ] Smart SM00126 IL6 [EMBL] Prodom PD004356 Interleukin_6[INRA-Toulouse] P05231 IL6_HUMAN [ Domain structure ] P05231 IL6_HUMAN [ sequences sharing Prodom at least 1 domain ] Blocks P05231

Atlas Genet Cytogenet Oncol Haematol 2007; 3 459 PDB 1ALU [ SRS ] 1ALU [ PdbSum ], 1ALU [ IMB ] 1ALU [ RSDB ] PDB 1IL6 [ SRS ] 1IL6 [ PdbSum ], 1IL6 [ IMB ] 1IL6 [ RSDB ] PDB 1N2Q [ SRS ] 1N2Q [ PdbSum ], 1N2Q [ IMB ] 1N2Q [ RSDB ] PDB 1P9M [ SRS ] 1P9M [ PdbSum ], 1P9M [ IMB ] 1P9M [ RSDB ] PDB 2IL6 [ SRS ] 2IL6 [ PdbSum ], 2IL6 [ IMB ] 2IL6 [ RSDB ] HPRD P05231 Protein Interaction databases DIP P05231 IntAct P05231 Polymorphism : SNP, mutations, diseases OMIM 147620;148000;166710 [ map ] GENECLINICS 147620;148000;166710 SNP IL6 [dbSNP-NCBI] SNP NM_000600 [SNP-NCI] SNP IL6 [GeneSNPs - Utah] IL6] [HGBASE - SRS] HAPMAP IL6 [HAPMAP] General knowledge Family IL6 [UCSC Family Browser] Browser SOURCE NM_000600 SMD Hs.654458 SAGE Hs.654458 GO neutrophil apoptosis [Amigo] neutrophil apoptosis GO cytokine activity [Amigo] cytokine activity GO interleukin-6 receptor binding [Amigo] interleukin-6 receptor binding GO protein binding [Amigo] protein binding GO extracellular region [Amigo] extracellular region GO extracellular space [Amigo] extracellular space GO acute-phase response [Amigo] acute-phase response GO humoral immune response [Amigo] humoral immune response cell surface receptor linked signal transduction [Amigo] cell surface receptor linked GO signal transduction GO cell-cell signaling [Amigo] cell-cell signaling GO positive regulation of cell proliferation [Amigo] positive regulation of cell proliferation GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation GO negative regulation of apoptosis [Amigo] negative regulation of apoptosis negative regulation of chemokine biosynthetic process [Amigo] negative regulation of GO chemokine biosynthetic process positive regulation of T-helper 2 cell differentiation [Amigo] positive regulation of T- GO helper 2 cell differentiation positive regulation of protein biosynthetic process [Amigo] positive regulation of GO protein biosynthetic process BIOCARTA Low-density lipoprotein (LDL) pathway during atherogenesis [Genes] BIOCARTA Cells and Molecules involved in local acute inflammatory response [Genes] BIOCARTA Cytokine Network [Genes]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 460 BIOCARTA Erythrocyte Differentiation Pathway [Genes] BIOCARTA Role of ERBB2 in Signal Transduction and Oncology [Genes] BIOCARTA IL-10 Anti-inflammatory Signaling Pathway [Genes] BIOCARTA IL 17 Signaling Pathway [Genes] BIOCARTA Signal transduction through IL1R [Genes] BIOCARTA IL 5 Signaling Pathway [Genes] BIOCARTA IL 6 signaling pathway [Genes] BIOCARTA Cytokines and Inflammatory Response [Genes] BIOCARTA Regulation of hematopoiesis by cytokines [Genes] PubGene IL6 Other databases Probes Probe IL6 Related clones (RZPD - Berlin) PubMed PubMed 499 Pubmed reference(s) in LocusLink Bibliography Identification of the human 26-kD protein, interferon beta 2 (IFN-beta 2), as a B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. Van Damme J, Opdenakker G, Simpson RJ, Rubira MR, Cayphas S, Vink A, Billiau A, Van Snick J. J Exp Med. 1987; 165(3): 914-919. Medline 2948184

Haemopoietic receptors and helical cytokines. Bazan JF. Immunol. Today 1990; 11: 350-354. (REVIEW).

IL-6-regulated transcription factors. Akira S. Int J Biochem Cell Biol. 1997; 29(12): 1401-1418. (REVIEW). Medline 9570135

Interleukin-6: structure-function relationships. Simpson RJ, Hammacher A, Smith DK, Matthews JM, Ward LD. Protein Sci. 1997; 6(5): 929-955. (REVIEW). Medline 9144766

Enhanced GBX2 expression stimulates growth of human prostate cancer cells via transcriptional up-regulation of the interleukin 6 gene. Gao AC, Lou W, Isaacs JT. Clin Cancer Res. 2000; 6(2): 493-497. Medline 10690529

Regulation of interleukin-6 secretion from breast cancer cells and its clinical implications. Kurebayashi J. Breast Cancer. 2000; 7(2):124-129. (REVIEW). Medline 11029783

IL-6-like cytokines and cancer cachexia: consequences of chronic inflammation. Barton BE. Immunol Res. 2001; 23(1):41-58. (REVIEW).

Atlas Genet Cytogenet Oncol Haematol 2007; 3 461 Medline 11417859

Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth. Culig Z, Bartsch G, Hobisch A. Mol Cell Endocrinol. 2002; 197(1-2):231-238. (REVIEW). Medline 12431817

Drug resistance and drug development in multiple myeloma. Dalton WS. Semin Oncol. 2002; 29(6 Suppl 17):21-25. (REVIEW). Medline 12520481

The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Purohit A, Newman SP, Reed MJ. Breast Cancer Res. 2002; 4(2):65-69. (REVIEW). Medline 11879566

Role of the androgen receptor axis in prostate cancer. Culig Z. Urology. 2003; 62(5 Suppl 1):21-26. (REVIEW). Medline 14607214

Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Biochem J. 2003; 374(Pt 1): 1-20. Medline 12773095

Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation. Ishikawa H, Tsuyama N, Abroun S, Liu S, Li FJ, Otsuyama K, Zheng X, Kawano MM. Leuk Lymphoma. 2003; 44(9):1477-1481. (REVIEW). Medline 14565647

Survival and proliferation factors of normal and malignant plasma cells. Klein B, Tarte K, Jourdan M, Mathouk K, Moreaux J, Jourdan E, Legouffe E, De Vos J, Rossi JF. Int J Hematol. 2003; 78(2):106-113. (REVIEW). Medline 12953803

Effects of all-trans retinoic acid (ATRA) on human myeloma cells. Otsuki T, Sakaguchi H, Hatayama T, Wu P, Takata A, Hyodoh F. Leuk Lymphoma. 2003; 44(10):1651-1656. (REVIEW). Medline 14692515

Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Trikha M, Corringham R, Klein B, Rossi JF. Clin Cancer Res. 2003; 9(13): 4653-4665. (REVIEW) Medline 14581334

The interleukin-6 gene: a susceptibility factor that may contribute to racial and ethnic disparities in breast cancer mortality. Berger FG. Breast Cancer Res Treat. 2004; 88(3):281-285. (REVIEW). Medline 15609131

Atlas Genet Cytogenet Oncol Haematol 2007; 3 462

Advances in biology of multiple myeloma: clinical applications. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Blood. 2004; 104(3):607-618 (REVIEW). Medline 15090448

Immunomodulation of multiple myeloma. Tohnya TM, Figg WD. Cancer Biol Ther. 2004;3(11):1060-1061. (REVIEW). Medline 15640623

Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Atreya R, Neurath MF. Clin Rev Allergy Immunol. 2005; 28(3): 187-196. (REVIEW). Medline 16129903

Interleukin-6 regulation of prostate cancer cell growth. Culig Z, Steiner H, Bartsch G, Hobisch A. J Cell Biochem. 2005; 95(3):497-505. (REVIEW). Medline 15838876

Bortezomib (Velcade)--a new therapeutic strategy for patients with refractory multiple myeloma. Goranov SE, Goranova-Marinova VS. Folia Med (Plovdiv). 2005; 47(3-4):11-9. (REVIEW). Medline 16761388

The role of IL-6 and STAT3 in inflammation and cancer. Hodge DR, Hurt EM, Farrar WL. Eur J Cancer. 2005; 41(16): 2502-2512. (REVIEW). Medline 16199153

Interleukin-6: from basic science to medicine--40 years in immunology. Kishimoto T. Annu Rev Immunol. 2005; 23: 1-21. (REVIEW). Medline 15771564

HLXB9 activates IL6 in Hodgkin lymphoma cell lines and is regulated by PI3K signalling involving E2F3. Nagel S, Scherr M, Quentmeier H, Kaufmann M, Zaborski M, Drexler HG, MacLeod RA. Leukemia. 2005; 19(5): 841-846. Medline 15772702

Signalling and survival pathways in multiple myeloma. Bommert K, Bargou RC, Stuhmer T. Eur J Cancer. 2006; 42(11):1574-1580. (REVIEW). Medline 16797970

Androgen axis in prostate cancer. Culig Z, Bartsch G. J Cell Biochem. 2006; 99(2):373-381. (REVIEW). Medline 16598769

Related Mitogenic signals initiated via interleukin-6 receptor complexes in cooperation with

Atlas Genet Cytogenet Oncol Haematol 2007; 3 463 other transmembrane molecules in myelomas. Ishikawa H, Tsuyama N, Obata M, Kawano M. J Clin Exp Hematop. 2006; 46(2):55-66. (REVIEW). Medline 17142955

Cytokines in breast cancer. Nicolini A, Carpi A, Rossi G. Cytokine Growth Factor Rev. 2006; 17(5):325-337. (REVIEW). Medline 16931107

Interleukin-6 trans-signalling in chronic inflammation and cancer. Scheller J, Ohnesorge N, Rose-John S. Scand J Immunol. 2006; 63(5): 321-329. (REVIEW). Medline 16640655

Interleukin-6 and its receptor: from bench to bedside. Scheller J, Rose-John S. Med Microbiol Immunol (Berl). 2006; 195(4): 173-183. (REVIEW). Medline 16741736

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 03-2007 Stefan Nagel, Roderick A F MacLeod Citation This paper should be referenced as such : Nagel S, MacLeod RAF . IL6 (interleukin 6 (interferon beta 2)). Atlas Genet Cytogenet Oncol Haematol. March 2007 . URL : http://AtlasGeneticsOncology.org/Genes/IL6ID519ch7p15.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 464 Atlas of Genetics and Cytogenetics in Oncology and Haematology

ALOX12 (Arachidonate 12-Lipoxygenase) Homo sapiens Identity Other names 12-LOX 12S-type 12(S)-lipoxygenase EC 1.13.11.31 LOG12 Hugo ALOX12 Location 17p13.1 According to NCBI Map Viewer, genes flanking ALOX15 in centromere to telomere direction on 17p13 are: GABARAP 17p13.1 GABA(A) receptor-associated protein, Local_order ASGR2 asialoglycoprotein receptor 2, ALOX12 17p13.1 arachidonate 12-lipoxygenase (Homo sapiens), ALOX12P2 17p13 arachidonate 12-lipoxygenase pseudogene 2, TEKT1 tektin 1, FBXO39 F-box protein 39. Note Arachidonate 12-Lipoxygenase (12-LOX) is one of several LOX isoforms that has iron as a cofactor and oxygenates polyunsaturated fatty acids. This particular isoform was also the first documented LOX in the animal kingdom. DNA/RNA Note With the exception of ALOX5, all human LOX genes, including ALOX12, are clustered on the short arm of chromosome 17 within a few megabases of each other. ALOX15, which has 86% sequence homology to ALOX12, is in closest proximity (17p13.2). Since chromosome 17 is known for gene duplications, the multiple LOX genes on the same chromosome may be as a result of such duplications.

Diagram of the ALOX12 gene. Exons are represented by grey boxes (in scale) untranscribed sequences in black, with exon numbers on the bottom.

Description According to Entrez-Gene, ALOX12 gene maps to NC_000017.9 and spans a region of 16.1 kilo bases. According to Spidey (mRNA to genomic sequence alignment tool), ALOX15 has 14 exons, the sizes being 168, 202, 82, 123, 104, 161, 144, 210, 87, 170, 122, 101, 171 and 490 bp. Transcription ALOX12 mRNA NM_000697 has 2335bp. Characterization of the 5' flanking region of the human ALOX12 in epidermoid carcinoma A431 cells indicated the presence of two Sp1 recognition motifs residing at -158 to -150 bp and -123 to -114 bp which are essential for gene expression. The proposed mechanism of action is as follows: epidermal growth factor induces MAPK activation in cells, followed by the activation of JUN/AP1. The biosynthesis of c- Jun is thereby increased. Sp1 recruits HDAC1 together with c-Jun to the gene promoter. When Sp1 is deacetylated it interacts with acetylate histone 3, following which p300 is recruited to the gene promoter leading to the enhancement of the

Atlas Genet Cytogenet Oncol Haematol 2007; 3 465 expression of 12(S)-lipoxygenase . Pseudogene According to Entrez Gene the arachidonate 12-lipoxygenase pseudogene (ALOX12P2) (HGNC: 13742) is located on 17p13.1. This is the "epidermal type" 12- LOX (e-12LO) that was cloned using a murine e-LO12 probe. Humans express this functional pseudogene in the skin and hair follicles. Protein Note 12S-lipoxygenases has three isoforms, named after their site of initial identification: platelet, leukocyte and epidermis. The leukocyte-type enzyme is expressed widely, while the platelet and epidermal enzymes are present in only a relatively limited number of cell types. Owing to the similarities in their genetic location, sequence and biological activities, leukocyte 12-LOX and 15-LOX-1 are often referred to as 12/15 lipoxygenase. Description 12-LOX protein consists of 662 amino acids, with a molecular weight of 75536 Da and contains non heme iron as a cofactor. According to the NCBI conserved domain search, the presence of a polycystin/lipoxygenase/alpha-toxin (PLAT) domain in the 12-LOX protein allows it access and enables it to catalyze enzymatic lipid peroxidation in complex biological structures via direct dioxygenation of phospholipids and cholesterol esters of biomembranes and plasma lipoproteins. The same conserved domain in 15-LOX-1 also enables it to oxidize complex lipids. Although cytosolic, both types of enzymes need this domain to access their sequestered membrane or micelle bound substrates. Expression The platelet type 12-LOX is expressed in the platelets and skin in humans. Based on structural and enzymatic properties, 15-LOX-1 is said to be a homolog of leukocyte type 12-LOX and are both expressed in mast cells, eosinophils, activated monocytes or dendritic cells, and bronchial epithelial cells. Localisation All 12-LOX isoforms have been localized to the cytoplasm. In addition, the platelet- type 12S-lipoxygenase was found in both cytosol and microsomal fractions of epidermal cells of human skin. Function 12-LOX is a member of the inflammatory leukotriene biosynthesis pathway where, in presence of molecular oxygen, it converts arachidonic acid to 12- hydroxyeicosatetraenoic acid (12-HETE). The leukocyte type 12-LOX can, in addition, effectively oxygenate linoleic acid and phospholipids. This isoform can also generate significant amounts of the 15-LOX product in addition to 12-HETE. Homology C. familiaris: LOC479476 similar to arachidonate 12-lipoxygenase, P. troglodytes: ALOX12, R. norvegicus: Alox12 (predicted), M. musculus: Alox12 arachidonate 12- lipoxygenase (12/15LOX), D. rerio: wufb72a11. Implicated in Entity Inflammation and cancer Note End product of arachidonic acid metabolism by the platelet-type 12-LOX 12(S)- Hydroxy eicosatetraenoic acid (12(S)-HETE) is shown to induce invasion, motility, and angiogenesis and protect tumour cells from apoptosis. Great many biological activities of 12(S)-HETE appear to be partly mediated by the activation of NF-kappaB. NF- kappaB is a family of five DNA binding proteins that regulate the expression of a variety of genes involved in host immune responses and inflammation. A direct relationship between platelet-type 12-LOX overexpression and NF-kappaB activation is reported in prostate cancer cells.

Entity Polymorphisms associated with diseases Note Aberrant arachidonic acid metabolism by 12-lipoxygenase (12-LOX) is implicated in carcinogenesis. Genetic polymorphisms 12-LOX is therefore thought to influence its function and/or expression and may modify the risk for colorectal adenoma. One of the single nucleotide polymorphisms (SNPs) reported in the 12-LOX gene located in exon 6 resulting in an Arg to Gln substitution at amino acid 261 of 12-LOX is in a highly conserved region of the lipoxygenase domain. Data from a community-based, case-

Atlas Genet Cytogenet Oncol Haematol 2007; 3 466 control study of incident, sporadic colorectal adenoma that included 162 cases and 211 controls have shown an inverse association between the Arg261Gln polymorphism in 12-LOX and colorectal adenoma (OR, 0.63; 95% CI, 0.40-1.00). A significant interaction also is observed between the 12-LOX polymorphism (Arg261Gln) and the use of nonsteroidal anti-inflammatory drugs. Another study argues that Gln261Arg in ALOX12 does not appear to be associated with colon cancer risk. Studies have shown higher urinary excretion of the arachidonic acid-derived metabolite 12-(S)hydroxyeicosatetraenoic acid (12(S)-HETE) in essential hypertension. For analysis of the association of polymorphisms in ALOX12 with hypertension and urinary levels of 12(S)-HETE, a study with 200 patients with essential hypertension and 166 matched controls is performed and as a result, the distribution of genotypes of the R261Q (Arg to Gln) polymorphism is found to be significantly different between patients and controls. These results indicate that a nonsynonymous polymorphism in ALOX12 is associated to essential hypertension and to urinary levels of 12(S)-HETE. Peak BMD is a major determinant of osteoporosis which is a complex disease with both genetic and environmental risk factors. In a population - and family - based association study of ALOX15 and ALOX12, SNPs distributed across the two genes are genotyped. Moderate evidence of association is found between spine BMD and six SNPs in the ALOX12 gene in both men and women. These data conclude that polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.

Entity Alzheimer's disease Note Alzheimer's disease (AD) is a chronic neurodegenerative disorder that impairs cognition and behavior. Although the initiating molecular events are not known, increasing evidence suggests that 12/15-LOX is a major source of oxidative stress which could play a functional role in pathogenesis. Quantitative Western blot analysis confirmed by immunohistochemical studies demonstrate that in affected frontal and temporal regions of AD brains, the amount of 12/15-LOX is higher compared to controls. Also metabolic products of 12/15-LOX are markedly elevated in AD brains compared to controls.

Entity Bladder cancer Note 12-LOX expression is shown to be induced in bladder cancer tissues by an immunohistochemistry analysis. Also lipoxygenase inhibitors cause marked inhibition of bladder cancer cells in a concentration and time dependent manner. Cells treated with lipoxygenase inhibitors show chromatin condensation, cellular shrinkage, small membrane bound bodies (apoptotic bodies) and cytoplasmic condensation.

Entity Testicular cancer Note 12-LOX is only slightly expressed in normal testis tissues, however, 12-LOX expression is found to be significant in testicular cancer tissues by immunohistochemistry studies. Specific LOX inhibitors have also been shown to inhibit the growth of testicular cancer in cell lines.

Entity Prostate cancer Note Research focusing on mechanisms of action of 12-lipoxygenase in prostate cancer cells revealed that overexpression of 12-lipoxygenase in PC-3 cells results in a 3-fold increase in VEGF protein level when compared with vector control cells and there is an increase in PI3-kinase activity in 12-LOX-transfected PC-3 cells. The expression of 12-LOX is detected to be low in benign prostatic hyperplasia and normal prostate tissues, whereas marked expression of 12-lipoxygenase is detected in prostatic intraepithelial neoplasia and prostate cancer tissues. The LOX inhibitors cause marked cellular death through apoptosis in prostate cancer cells in a

Atlas Genet Cytogenet Oncol Haematol 2007; 3 467 concentration and time-dependent manner. Another effect of 12-LOX in prostate cancer cells is that increase in 12-LOX expression enhances the metastatic potential of human prostate cancer cells. 12-LOX transfected PC-3 cells show a significant change in cell adhesiveness, spreading, motility, and invasiveness.

Entity Breast cancer Note Total cellular RNA extraction from 64 frozen tissue samples of breast carcinoma and their corresponding normal adjacent tissues is performed for expression analysis of cyclooxygenase-2 and 12-lipooxygenase using RT-PCR. 62.5% of carcinoma samples showed over-expression of 12-lipooxygenase as compared to normal breast tissues. Results also reveal that and 12-lipooxygenase mRNA expressions are associated with TNM staging in human breast cancer. A second study indicates that levels of 12- lipoxygenases together with 5-lipoxygenase are also particularly high in tumours from patients who died of breast cancer. Therefore raised level of 12-lipoxygenase might have prognostic value in patients with breast cancer.

External links Nomenclature Hugo ALOX12 GDB ALOX12 Entrez_Gene ALOX12 239 arachidonate 12-lipoxygenase Cards Atlas ALOX12ID620ch17p13 GeneCards ALOX12 Ensembl ALOX12 Genatlas ALOX12 GeneLynx ALOX12 eGenome ALOX12 euGene 239 Genomic and cartography GoldenPath ALOX12 - 17p13.1 chr17:6840128-6854776 + 17p13.1 (hg18-Mar_2006) Ensembl ALOX12 - 17p13.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene ALOX12 Gene and transcription Genbank AF143883 [ ENTREZ ] Genbank BC069557 [ ENTREZ ] Genbank M35418 [ ENTREZ ] Genbank M58704 [ ENTREZ ] Genbank M62982 [ ENTREZ ] RefSeq NM_000697 [ SRS ] NM_000697 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010718 [ SRS ] NT_010718 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 3 468 RefSeq NW_926584 [ SRS ] NW_926584 [ ENTREZ ] AceView ALOX12 AceView - NCBI Unigene Hs.654431 [ SRS ] Hs.654431 [ NCBI ] HS654431 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P18054 [ SRS] P18054 [ EXPASY ] P18054 [ INTERPRO ] Prosite PS00711 LIPOXYGENASE_1 [ SRS ] PS00711 LIPOXYGENASE_1 [ Expasy ] Prosite PS00081 LIPOXYGENASE_2 [ SRS ] PS00081 LIPOXYGENASE_2 [ Expasy ] Prosite PS50095 PLAT [ SRS ] PS50095 PLAT [ Expasy ] Interpro IPR008976 Lipase_LipOase [ SRS ] IPR008976 Lipase_LipOase [ EBI ] Interpro IPR000907 LipOase [ SRS ] IPR000907 LipOase [ EBI ] Interpro IPR013819 LipOase_C [ SRS ] IPR013819 LipOase_C [ EBI ] Interpro IPR001024 LipOase_LH2 [ SRS ] IPR001024 LipOase_LH2 [ EBI ] Interpro IPR001885 Mammal_lipOase [ SRS ] IPR001885 Mammal_lipOase [ EBI ] CluSTr P18054 Pfam PF01477 PLAT [ SRS ] PF01477 PLAT [ Sanger ] pfam01477 [ NCBI-CDD ] Smart SM00308 LH2 [EMBL] Blocks P18054 HPRD P18054 Protein Interaction databases DIP P18054 IntAct P18054 Polymorphism : SNP, mutations, diseases OMIM 152391 [ map ] GENECLINICS 152391 SNP ALOX12 [dbSNP-NCBI] SNP NM_000697 [SNP-NCI] SNP ALOX12 [GeneSNPs - Utah] ALOX12] [HGBASE - SRS] HAPMAP ALOX12 [HAPMAP] General knowledge Family ALOX12 [UCSC Family Browser] Browser SOURCE NM_000697 SMD Hs.654431 SAGE Hs.654431 1.13.11.31 [ Enzyme-SRS ] 1.13.11.31 [ Brenda-SRS ] 1.13.11.31 [ KEGG Enzyme ] 1.13.11.31 [ WIT ] GO arachidonate 12-lipoxygenase activity [Amigo] arachidonate 12-lipoxygenase activity GO arachidonate 12-lipoxygenase activity [Amigo] arachidonate 12-lipoxygenase activity GO iron ion binding [Amigo] iron ion binding GO cytosol [Amigo] cytosol GO electron transport [Amigo] electron transport oxygen and reactive oxygen species metabolic process [Amigo] oxygen and reactive GO oxygen species metabolic process GO anti-apoptosis [Amigo] anti-apoptosis

Atlas Genet Cytogenet Oncol Haematol 2007; 3 469 GO anti-apoptosis [Amigo] anti-apoptosis GO cell motility [Amigo] cell motility GO positive regulation of cell proliferation [Amigo] positive regulation of cell proliferation GO positive regulation of cell proliferation [Amigo] positive regulation of cell proliferation GO lipoxygenase activity [Amigo] lipoxygenase activity GO activity [Amigo] oxidoreductase activity GO leukotriene biosynthetic process [Amigo] leukotriene biosynthetic process GO fatty acid oxidation [Amigo] fatty acid oxidation GO positive regulation of cell growth [Amigo] positive regulation of cell growth GO sarcolemma [Amigo] sarcolemma GO superoxide release [Amigo] superoxide release GO positive regulation of cell adhesion [Amigo] positive regulation of cell adhesion GO metal ion binding [Amigo] metal ion binding GO hepoxilin-epoxide hydrolase activity [Amigo] hepoxilin-epoxide hydrolase activity KEGG Prostaglandin and Leukotriene Metabolism PubGene ALOX12 Other databases Probes Probe ALOX12 Related clones (RZPD - Berlin) PubMed PubMed 48 Pubmed reference(s) in LocusLink Bibliography Investigation of the oxygenation of phospholipids by the porcine leukocyte and human platelet arachidonate 12-lipoxygenases. Takahashi Y, Glasgow WC, Suzuki H, Taketani Y, Yamamoto S, Anton M, Kuhn H, Brash AR. Eur J Biochem. 1993; 218: 165-171. Medline 8243462

Arachidonate 12-lipoxygenase. Yoshimoto T, Yamamoto S. J Lipid Mediat Cell Signal. 1995; 12(2-3): 195-212. Medline 8777566

Transcriptional activation of human 12-lipoxygenase gene promoter is mediated through Sp1 consensus sites in A431 cells. Liu YW, Arakawa T, Yamamoto S, Chang WC. Biochem J. 1997; 324 (1): 133-140. Medline 9164849

Cloning of a human epidermal-type 12-lipoxygenase-related gene and chromosomal localization to 17p13. Sun D, Elsea SH, Patel PI, Funk CD. Cytogenet Cell Genet. 1998; 81(1): 79-82. Medline 9691181

Characterization of epidermal 12(S) and 12(R) lipoxygenases. McDonnell M, Li H, Funk CD. Adv Exp Med Biol. 2002; 507: 147-153.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 470 Medline 12664578

Levels of expression of lipoxygenases and cyclooxygenase-2 in human breast cancer. Jiang WG, Douglas-Jones A, Mansel RE. Prostaglandins Leukot Essent Fatty Acids. 2003; 69: 275-281. Medline 12907138

Platelet-type 12-lipoxygenase activates NF-kappaB in prostate cancer cells. Kandouz M, Nie D, Pidgeon GP, Krishnamoorthy S, Maddipati KR, Honn KV. Prostaglandins Other Lipid Mediat. 2003; 71: 189-204 Medline 14518561

Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12-lipoxygenase. Nie D, Nemeth J, Qiao Y, Zacharek A, Li L, Hanna K, Tang K, Hillman GG, Cher ML, Grignon DJ, Honn KV. Clin Exp Metastasis. 2003; 20: 657-663. Medline 14669797

Expression of lipoxygenase in human bladder carcinoma and growth inhibition by its inhibitors. Yoshimura R, Matsuyama M, Tsuchida K, Kawahito Y, Sano H, Nakatani T. J Urol. 2003; 170: 1994-1999. Medline 14532840

Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk. Goodman JE, Bowman ED, Chanock SJ, Alberg AJ, Harris CC. Carcinogenesis. 2004; 25: 2467-2472. Medline 15308583

Expression of lipoxygenase in human prostate cancer and growth reduction by its inhibitors. Matsuyama M, Yoshimura R, Mitsuhashi M, Hase T, Tsuchida K, Takemoto Y, Kawahito Y, Sano H, Nakatani T. Int J Oncol. 2004; 24: 821-827. Medline 15010818

12/15-lipoxygenase is increased in Alzheimer's disease: possible involvement in brain oxidative stress. Pratico D, Zhukareva V, Yao Y, Uryu K, Funk CD, Lawson JA, Trojanowski JQ, Lee VM. Am J Pathol. 2004;164: 1655-1662. Medline 15111312

Relationship between lipoxygenase and human testicular cancer. Yoshimura R, Matsuyama M, Mitsuhashi M, Takemoto Y, Tsuchida K, Kawahito Y, Sano H, Nakatani T. Int J Mol Med. 2004; 13: 389-393. Medline 14767568

Transcription factor Sp1 functions as an anchor protein in gene transcription of human 12(S)- lipoxygenase. Chang WC, Chen BK. Biochem Biophys Res Commun. 2005; 338(1): 117-121. Medline 16122700

Atlas Genet Cytogenet Oncol Haematol 2007; 3 471

Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription. Hung JJ, Wang YT, Chang WC. Mol Cell Biol. 2006; 26(5): 1770-1785. Medline 16478997

Human ALOX12, but not ALOX15, is associated with BMD in white men and women. Ichikawa S, Koller DL, Johnson ML, Lai D, Xuei X, Edenberg HJ, Klein RF, Orwoll ES, Hui SL, Foroud TM, Peacock M, Econs MJ. J Bone Miner Res. 2006; 21: 556-564. Medline 16598376

Expression of cyclooxygenase-2 and 12-lipoxygenase in human breast cancer and their relationship with HER-2/neu and hormonal receptors: impact on prognosis and therapy. Mohammad AM, Abdel HA, Abdel W, Ahmed AM, Wael T, Eiman G. Indian J Cancer. 2006; 43: 163-168. Medline 17192687

Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells. Nie D, Krishnamoorthy S, Jin R, Tang K, Chen Y, Qiao Y, Zacharek A, Guo Y, Milanini J, Pages G, Honn KV. J Biol Chem. 2006 ;281: 18601-18609. Medline 16638750

A coding polymorphism in the 12-lipoxygenase gene is associated to essential hypertension and urinary 12(S)-HETE. Quintana LF, Guzman B, Collado S, Claria J, Poch E. Kidney Int. 2006; 69: 526-530. Medline 16514435

Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer. Tan W, Wu J, Zhang X, Guo Y, Liu J, Sun T, Zhang B, Zhao D, Yang M, Yu D, Lin D. Carcinogenesis. 2006 Dec 6. Medline 17151091

Common polymorphisms in 5-lipoxygenase and 12-lipoxygenase genes and the risk of incident, sporadic colorectal adenoma. Gong Z, Hebert JR, Bostick RM, Deng Z, Hurley TG, Dixon DA, Nitcheva D, Xie D. Cancer. 2007; 109: 849-857. Medline 17236225

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Search in all EBI

Contributor(s) Written 03-2007 Sreeparna Banerjee, Asli Erdog Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2007; 3 472 Banerjee S, Erdog A . ALOX12 (Arachidonate 12-Lipoxygenase) Homo sapiens. Atlas Genet Cytogenet Oncol Haematol. March 2007 . URL : http://AtlasGeneticsOncology.org/Genes/ALOX12ID620ch17p13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 473

Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(5;12)(q31;p13) in MDS, AML and AEL Clinics and Pathology Disease The t(5;12)(q31;p13) translocation involving ETV6 (12p13) and ACSL6 (5q31) was found in a patient with refractory anemia with excess blasts (RAEB) with basophilia, a patient with acute myelogenous leukemia (AML) with eosinophilia, and a patient with acute eosinophilic leukemia (AEL). Phenotype / cell stem Myeloid lineage origin Epidemiology To date, one case with myelodysplastic syndrome (RAEB), one case with AML, one case with AEL, one case with atypical CML, and 2 cases with Polycythemia Vera (PV). The t(5;12)(q31;p13) is a recurrent translocation in myeloid malignancies (at least 23 cases reported). Prognosis No prognostic value established. Cytogenetics Cytogenetics May be not easy to detect. Morphological Cytogenetics The translocation can be detected by FISH with ETV6 probes. The ETV6 gene is Molecular rearranged, and the breakpoint is between exon 1 and exon 2 in all cases reported. Additional Disruption of the second ETV6 allele by t(12;19) was detected in the AML case by anomalies FISH analysis. Variants No variants Genes involved and Proteins Gene Name ETV6 (ETS Variant gene 6) Location 12p13 Note The gene is known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma . Dna / Rna 9 exons; alternate splicing Protein The gene encodes an ETS family transcription factor; the product of this gene contains a N-terminal pointed (PNT) domain that is involved in the protein-protein interactions, and a C-terminal ETS DNA-binding domain; wide expression; nuclear localization. Gene Name ACSL6 (Acyl-CoA Synthetase Long-chain family member 6) Location 5q31 Note None of the resulting chimeric transcripts, except for the ACSL6/ETV6 transcript in the RAEB case, led to a fusion protein. Dna / Rna 57,74 kb, 21 exons; alternate splicing Protein Two splicing isoforms, a long and a short. The gene encodes an AMP binding enzyme; plays an important role in fatty acid metabolism in brain, responsible for activation of long-chain fatty acids in erythrocytes. Wide expression, expression low at earlier stages of erythroid development but very high in reticulocytes. Result of the chromosomal anomaly

Atlas Genet Cytogenet Oncol Haematol 2007; 3 474 Hybrid gene A novel human gene, called ACS2 (acyl-CoA synthetase-2), was identified as an ETV6 Description fusion partner in a recurrent t(5;12)(q31;p13) translocation. Northern blot analysis detected high levels of ACS2 expression in brain, fetal liver, and bone marrow, and the gene was found to be highly conserved in man and rat. The ETV6/ACSL6 fusion transcripts showed an out-frame fusion of exon 1 of ETV6 to exon 1 of ACSL6 in the AEL patient, an out-frame fusion of exon 1 of ETV6 to exon 11 of ACSL6 in the AML patient, and a short in-frame fusion of exon 1 of ETV6 to the 3-prime untranslated region of ACSL6 in the patient with RAEB. Reciprocal ACSL6/ETV6 transcripts were identified in 2 of the cases. FISH with ETV6 cosmids on 12p13, and BACs and PIs on 5q31, demonstrated that the 5q31 breakpoints of the AML and AEL cases involved the 5-prime portion of the ACSL6 gene, and that the 5q31 breakpoint of the RAEB case involved the 3-prime portion of the ACSL6 gene. None of the resulting chimeric transcripts except for the ACSL6/ETV6 transcript in the RAEB case led to a fusion protein. A case with a CML and a t(5;12)(q31;p13) was characterized, and 3 different ETV6/ACSL6 transcripts were detected. Moreover, as a consequence of the translocation IL-3/CSF2, located at 5q31, was ectopically expressed in the leukemic cells.

External links Other t(5;12)(q31;p13) in MDS, AML and AEL Mitelman database (CGAP - NCBI) database Other t(5;12)(q31;p13) in MDS, AML and AEL CancerChromosomes (NCBI) database Bibliography Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, Kobayashi H, Terasaki H, Ohyashiki K, Asou N, Murohashi I, Bessho M, Hirashima K. Genes Chromosomes Cancer. 1999; 26: 192-202. Medline 10502316

Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13). Cools J, Mentens N, Odero MD, Peeters P, Wlodarska I, Delforge M, Hagemeijer A, Marynen P. Blood. 2002; 99: 1776-1784. Medline 11861295 t(5;12)(q2331;p13) with ETV6-ACSL6 gene fusion in polycythemia vera. A Murati A, J Adelaide J, Gelsi-Boyer V, Etienne A, V Remy V, Fezoui H, Sainty D, L Xerri2,3, N Vey L, Olschwang S, Birnbaum D, Chaffanet M, Mozziconacci MJ. Leukemia. 2006; 20: 1175-1178. Medline 16572202

Contributor(s) Written 03-2007 Maria D. Odero Citation This paper should be referenced as such : Odero MD . t(5;12)(q31;p13) in MDS, AML and AEL. Atlas Genet Cytogenet Oncol Haematol. March 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0512q31p13ID1344.html

Atlas Genet Cytogenet Oncol Haematol 2007; 3 475 © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 476 Atlas of Genetics and Cytogenetics in Oncology and Haematology

i(8)(q10) in acute myeloid leukaemia Clinics and Pathology Disease Acute myeloid leukaemia (AML) Note The aberration has also been reported in many other neoplastic disorders, most notably T-prolymphocytic leukaemia (PLL) and acute lymphoblastic leukaemia (ALL). In the latter, it often occurs as a secondary event to the t(9;22). Phenotype / Has been reported to occur in all AML FAB types, with FAB M2 representing the most cell stem common morphology. origin Epidemiology A rare non-random event reported in over 50 cases of AML (below 0.5% of all cases) and occurs in both children and adults. Prognosis As the aberration is rare and will frequently occur in complex karyotypes, whether an independent prognosis association can be determined is uncertain. Cytogenetics Cytogenetics In approximately 40% of cases the aberration is reported as a chromosome gain. Morphological Probes Use of a centromere 8 probe combined with a C-MYC probe will help distinguish between gain of i(8)(q10) and simple chromosome 8 gain. Additional Seldom occurs as a primary karyotype event. Most often found in complex karyotypes anomalies and/or arises in a sub-clone. The complex karyotypes will frequently contain loss of (q) and/or loss of chromosome 7(q). External links Other i(8)(q10) in acute myeloid leukaemia Mitelman database (CGAP - NCBI) database Bibliography Deletions of the long arm of chromosome 7 in myeloid disorders: loss of band 7q32 implies worst prognosis. Rodrigues Pereira Velloso E, Michaux L, Ferrant A, Hernandez JM, Meeus P, Dierlamm J, Criel A, Louwagie A, Verhoef G, Boogaerts M, Michaux J-L, Bosly A, Mecucci C, Van den Berghe H. Br J Haematol 1996; 92: 574-581. Medline 8616020

Comparative genomic hybridization and conventional cytogenetic analyses in childhood acute myeloid leukemia. Leuk Lymphoma 1999; 35: 311-315. Medline 10706455

Wong KF, Kwong YL. Cancer Genet Cytogenet 2000; 120: 171-173. Medline 10991616

Cross-species color banding in ten cases of myeloid malignancies with complex karyotypes. Harrison CJ, Yang F, Butler T, Cheung K-L, O'Brien PC, Hennessy BJ, Prentice HG, Ferguson-Smith M. Genes Chromosomes Cancer 2001; 30: 15-24. Medline 11107171

Atlas Genet Cytogenet Oncol Haematol 2007; 3 477

Loss of i(8)(q10) at relapse in two cases of childhood acute myeloid leukaemia. Seppa L, Hengartner H, Leibundgut K, Kuhne T, Niggli FK, Betts DR. Leuk Lymphoma 2007 (in press).

Contributor(s) Written 03-2007 David Betts Citation This paper should be referenced as such : Betts D . i(8)(q10) in acute myeloid leukaemia. Atlas Genet Cytogenet Oncol Haematol. March 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/i8q10ID1334.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 478

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Vulva and Vagina tumors: an overview Classification Note Neoplasms of the vulva and vagina together account for less than 5% of all female genital tract cancers. Staging and grading of the lesions follows the TNM (Tumor, regional lymphoNode, Metastasis) and FIGO (International Federation of Gynecology and Obstetrics) recommendations. According to WHO recommendations, the main Vulva and Vagina categories are: VULVA NEOPLASIA: I. Epithelial neoplasms A. Squamous and related Tumors and precursors 1. Squamous cell carcinoma not otherwise specified 2. Basal cell carcinoma 3. Squamous intraepithelial neoplasia 4. Benign squamous lesions B. Glandular Tumors 1. Paget disease 2. Bartholin gland Tumors: carcinomas, adenoma and adenomyoma 3. Tumor arising from specialized ano-genital mammary-like glands 4. Adenocarcinoma of Shene gland origin 5. Adenocarcinoma of other types 6. Adenoma of minor vestibular glands 7. Mixed Tumors of the vulva 8. Tumors of skin appendage origin 1. Embryonal rhabdomyosarcoma (sarcoma botryoides) 2. Leiomyosarcoma 3. fibrous histiocytoma 4. Proximal epithelioid sarcoma 5. Alveolar soft part sarcoma 6. Liposarcoma 7. Dermatofibrosarcoma protuberans 8. Deep angiomyxoma 9. Superficial angiomyxoma 10. Angiomyofibroblastoma 11. Cellular angiofibroma 12. Leiomyoma 13. Granular cell Tumor 14. Other III. Melanocytic Tumors 1. Malignant melanoma 2. Congenital melanocytic naevus 3. Acquired melanocytic naevus 4. Blue naevus 5. Atypical melanocytic naevus of genital type 6. Dysplastic melanocytic naevus IV. Miscellaneous Tumors 1. Yolk sac Tumor 2. Merkel cell Tumor 3. Peripheral primitive neuroectodermal Tumor/Ewing sarcoma V. Haematopoietic and lymphoid Tumors 1. Malignant lymphoma

Atlas Genet Cytogenet Oncol Haematol 2007; 3 479 2. Leukemia VI. Secondary tumors

VAGINA NEOPLASIA:

I. Epithelial neoplasms A. Squamous Tumors and precursors 1. Squamous cell carcinoma not otherwise specified 2. Squamous intraepithelial neoplasia 3. Benign squamous lesions (condyloma acuminatum, squamous papilloma, fibroepithelial polyp) B.Glandular lesions 1. Adenocarcinoma, NOS 2. Clear cell adenocarcinoma 3. Endometrioid adenocarcinoma 4. Mucinous adenocarcinoma 5. Mesonephric adenocarcinoma 6. Mullerian papilloma 7. Adenoma not otherwise specified C.Other epithelial Tumors 1. Adenosquamous carcinoma 2. Adenoid cystic carcinoma 3. Adenoid basal carcinoma 4. Carcinoid 5. Small cell carcinoma 6. Undifferentiated carcinoma II. Mesenchymal Tumors 1. Sarcoma botryoides 2. Leiomyosarcoma 3. Endometrioid stromal sarcoma, low grade 4. Undifferentiated vaginal sarcoma 5. Alveolar soft part sarcoma 6. Leiomyoma 7. Deep angiomyxoma 8. Post-operative spindle nodule III. Mixed epithelial and mesenchymal Tumors 1. Carcinosarcoma (Malignant Mullerian Mixed tumors; metaplastic carcinoma) 2. Adenosarcoma 3. Malignant mixed Tumors resembling synovial sarcoma 4. Benign mixed Tumors IV. Melanocytic Tumors 1. Malignant melanoma 2. Blue naevus 3. Melanocytic naevus V. Miscellaneous Tumors A. Tumor of germ cell type 1. Yolk sac Tumor 2. Dermoid Cyst B. Others 1. Peripheral primitive neuroectodermal Tumor/Ewing sarcoma 2. Adenomatoid Tumor 3. Malignant lymphoma 4. Granulocytic sarcoma VI Secondary Tumors Clinics and Pathology Disease Tumor of the vulva and vagina Note Benign and malignant solid tumors at these sites are rare. The malignant lesions may

Atlas Genet Cytogenet Oncol Haematol 2007; 3 480 have epithelial (squamous and glandular) and mesenchymal (soft tissue) origin. Etiology The high-risk (HR) human papillomaviruses (HPVs) infections have been identified as an essential although not sufficient factor in the pathogenesis of vulval and vagina carcinoma. It has been demonstrated that HPV integration sites are distributed over the whole genome, with a preference for genomic fragile site. It has been also hypothesized that, at the early stages of infection, the virus genome, still in an not integrated state, expresses oncoproteins E6 and E7 which interfer with the mechanisms of chromosome segregation during mitosis. This phenomenon, would favour the virus genome integration into chromosomal DNA. However, no evidence for targeted disruption of critical cellular genes by the integrated viral sequences has been found. According to this, two categories of affected patients can be distinguhished: Malignant lesions of the vulva Older age (mean 77): no vulva intraepithelial neoplasia (VIN) pre-existing pre-malignant condition, not Human Papilloma Virus (HPV) related, unknown etiology. Younger age (mean 55): usually associated with VIN, HPV-related (usually type 16). Malignant lesions of the vagina The strongest association is between squamous cell carcinoma and HPV types 16 and 18 infection. Association with a pre-malignant lesion, known as vaginal intraepithelial neoplasia (VAIN), was reported. Association with previous history of cervical intraepithelial neoplasia (CIN), invasive cervical carcinoma, or invasive vulvar carcinoma has been reported. Epidemiology Malignant neoplasms of the vulva together with neoplasms of the vagina account for less than 5% of all genital tract cancers. Squamous cell carcinoma (approximately 90% and 80% of the malignant neoplasms of the vulva and the vagina, respectively) is the most commonly found, and it is primarily a disease of elderly women, although it may be also observed in premenopausal women. Pigmented vulvar and vaginal lesions may occur, including nevi and melanoma, which accounts for 9% of vulvar and 5% of vaginal malignant lesions. Diethylstilbestrol (DES)-Associated Disease of the vagina are described: DES is a synthetic non-steroidal estrogen used in the early 1970s to prevent miscarriage. The female fetuses delivered by the mothers taking DES suffered from severe vaginal lesions including vaginal adenosis (benign) and clear cell adenocarcinoma. Malignant mesenchimal tumors of the vulva or vagina are rare: leiomyosarcoma is the most common vulvar lesion (mean age 35), dermatofibrosarcoma is one of the rarest: 25 cases reported, mean age 54. Clinics Cancer of the vulva and vagina at the very early stages tends to be asymptomatic. Delay in diagnosis is common, partially due to disease rarity and to delay in relating patient symptoms to the disease origin. Vulva. Major symptoms are: painless bleeding unrelated to the menstrual cycle, appearing of vulvar skin white and rough. Vagina. Major symptoms are painless vaginal bleeding (65-80% of all cases), difficult or painful urination, pain in the pelvic area. Mainly post-menopausal women (70%) are affected. Many vulvar or vaginal growths are not neoplastic and may be treated by monitoring or simple excision. Suspicious growths require diagnostic biopsy and in case of cancer diagnosis surgical ablation is mandatory. Pathology The histopathology of vulva and vagina neoplasms reflect the different cell origins of the Tumors (see classification). Examples of both gross and microscopic images of these clinical entities can be viewed at Treatment Vulva. Small primary lesions less than 2 cm in diameter with superficial invasion are usually treated with wide local excision with adequate surgical margins For tumors larger than 2 cm, or deeply growing into the underlying inguinal, lymphadenectomy is performed in order to plan a further partial or total vulvectomy. Radiation, with or without chemotherapy, may be used to treat advanced tumors or tumor recurrences, although there is not general consensus on the advantage of post-operative radiation therapy. Vagina. According to the FIGO, a vaginal lesion arises solely from the vagina : a

Atlas Genet Cytogenet Oncol Haematol 2007; 3 481 vaginal lesion involving the external os of the cervix should be considered cervical cancer, and a tumor involving both vulva and vagina should be considered vulvar cancer, and they should be treated as such. Radiotherapy is the most commonly used treatment for cancer of the vagina. Indication for diverse surgical interventions (radical hysterectomy, total or subtotal vaginectomy, vulvectomy, inguinal lymphadenectomy, etc), often accompained by radiation therapy, depends on the lesion type, stage, location, size and patient¹s history. Prognosis Vulva. As with many other types of cancer prognosis depends on several factors, including the histological type of the lesion. In general, patients with increasing tumor stage have a lower rate of survival. The overall 5-year survival rate ranges from 90% to 33%, depending upon whether and how many lymphonodes are involved (not in a directly proportional way). Recurrences are seen in a high percentage of patients within the first two years of follow-up. Vagina. The histologic type, size (Tumors less than 4cm seem to be associated with a significantly better survival rate), stage and grade and location of the tumor influence the survival rate. The overall 5-year survival rate is about 61% , with about 54% survivig for 10 years or more. Cytogenetics Cytogenetics Data on cytogenetics of vulva and vagina cancer are scarse. Epithelial malignancy of Morphological both lesions show cytogenetic abnormalities, although no specific chromosome markers have been identified so far, and no consistent association between cytogenetic subgroups and histological differentiation have been observed. Complex karyotypes are frequent, however simple karyotypes have been observed in a number of cases as well. Cytogenetically unrelated clones, as well as closely related clones, were found in both in situ and infiltrating squamous cell carcinoma (SCC). Structural changes of chromosome 3,8,9,11,13,14,19 and 22 have been frequently observed. Cytogenetically unrelated, abnormal clones, characterized by simple changes (chromosome X and 7 aneuploidy) have been described in Paget¹s disease. The karyotypes of melanoma and dermatofibrosarcoma protuberans, arising in the vulva and/or vagina, substantially do not differ from the karyotypes of the same entities arising at other sites. A single case of vagina leiomyoma has been reported recently and a t(7;8)(p13;q11.2) translocation without PLAG1 alteration has been described. Cytogenetics Fluorescence in situ hybridization (FISH) supports the cytogenetic pattern observed by Molecular conventional techniques, confirming the gain of chromosome 3q as an early and consistent change in carcinomas of the vulva, and the presence of EWS/FLI-1 fusion in extraosseous Ewing's sarcoma/peripheral neuroectodermal tumors of both vulva and vagina. CGH profiles are also confirmatory: chromosome imbalance with gains from the long arm of chromosome 3,5,8,9 and losses from the 11q have been frequently observed. A comparison between papillomavirus-negative and papillomavirus-positive vulvar cancer indicated that chromosome 8q was more commonly gained in the positive cases. Genes involved and Proteins Note No specific genes involved in vulva or vagina carcinogenesis have been found so far. An isolated study indicated a prominent role of the common IL1RN intron 2 polymorphism in vulvar carcinogenesis.

External links Other website database

Bibliography

Atlas Genet Cytogenet Oncol Haematol 2007; 3 482 Karyotypic findings in tumors of the vulva and vagina. Teixeira MR, Kristensen GB, Abeler VM, Heim S. Cancer Genet Cytogenet. 1999; 111: 87-91. Medline 10326597

Primary vulvar and vaginal extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor: diagnostic confirmation with CD99 immunostaining and -polymerase chain reaction. Vang R, Taubenberger JK, Mannion CM, Bijwaard K, Malpica A, Ordonez NG, Tavassoli FA, Silver SA. Int J Gynecol Pathol. 2000; 19: 103-109. Medline 10782405

A case of Dermatofibrosarcoma protuberans of the vulva with a COL1A1/PDGFB fusion identical to a case of Giant Cell fibroblastoma. Vanni R, Faa G, Dettori T, Dumanski JP, O¹ Brien KP. Virchows Arch. 2000; 437: 95-100. Medline 10963386

Genetic aberrations detected by comparative genomic hybridisation in vulvar cancers. Allen DG, Hutchins AM, Hammet F, White DJ, Scurry JP, Tabrizi SN, Garland SM, Armes JE. Br J Cancer. 2002; 86: 924-928. Medline 11953825

WHO classification of tumours: 2002 editions Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Tavassoli FA and Stratton MR Editors

Cytogenetic characterization of tumors of the vulva and vagina. Micci F, Teixeira MR, Scheistroen M, Abeler VM, Heim. Genes Chromosomes Cancer. 2003; 38: 137-148. Medline 12939741

A polymorphism of the interleukin-1 receptor antagonist plays a prominent role within the interleukin-1 gene cluster in vulvar carcinogenesis. Grimm C, Berger I, Tomovski C, Zeillinger R, Concin N, Leodolter S, Koelbl H, Tempfer CB, Hefler LA. Gynecol Oncol. 2004; 92: 936-940. Medline 14984963

A clonal translocation (7;8)(p13;q11.2) in a leiomyoma of the vulva. Horton E, Dobin SM, Debiec-Rychter M, Donner RL. Cancer Genet Cytogenet. 2006; 170: 58-60. Medline 16965956

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 02-2007 Roberta Vanni, Giuseppina Parodo Citation This paper should be referenced as such : Vanni R, Parodo G . Vulva and Vagina tumors: an overview. Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Tumors/VulVaginaCarcID5274.html

Atlas Genet Cytogenet Oncol Haematol 2007; 3 483

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 484 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Carcinoma with t(15;19) translocation Identity Other names Mediastinal carcinoma with chromosome translocation t(15;19) Midline carcinoma of children and young adults with NUT rearrangement Midline carcinoma with t(15;19) Poorly differentiated carcinoma with t(15;19) Poorly differentiated thymic carcinoma t(15;19) positive tumor Clinics and Pathology Disease Carcinoma with t(15;19) translocation Phenotype / cell stem It has been suggested that tumor cells derive from early epithelial progenitor cells. origin Embryonic The majority of the cases presumably derive from various (midline) epithelial surfaces. origin One tumor, localized to the iliac bone and staining negative for epithelial, endothelial, germ cell and neuroendocrine markers has been reported, suggesting that the tumor might also derive from non-epithelial structures. Etiology Unknown Epidemiology A total of 13 cases have been reported to date. All tumors occurred in children or young adults with a median age of 15 years of age (range 3-35). There seem to be no sex predilection (8 males, 5 females). Clinics The growth pattern is typically aggressive and locally invasive. Metastatic growth is common in particular in bone, but also in lymph nodes and lungs. Cytology Focal reactivity with pan-cytokeratin markers. Negative for CD30, CD45, PLAP, HMB45, S100 and neuroendocrine markers. Pathology The tumor cells are typically undifferentiated, of intermediate size and the mitotic index is high. Treatment Intensive combined chemotherapy and occasionally radiotherapy. Prognosis Extremely poor. Among the cases reported so far, the median survival time was 18 weeks (range 6-67). It has been suggested that a critical prognostic difference exists between BRD4- NUT/t(15;19) positive tumors and tumors where NUT is rearranged but fused to an as yet unknown partner. Cytogenetics Cytogenetics The characteristic t(15;19) has been observed in all reported cases. The reported Morphological breakpoints on chromosome 15 have varied (15q11-q15). The breakpoints on clustered to 19p13 in the majority of the cases. In one case the breakpoint was interpreted as 19q13. Cytogenetics Various FISH protocols for the detection of 15q and 19p rearrangements, strongly Molecular indicating the presence of a t(15;19), have been reported. The material used has been paraffin-embedded sections of tumor biopsy or metaphase spreads of cultured tumor tissue. The t(15;19) is typically seen as the sole change. In one case a variant t(11;15;19) was reported. Probes Probes for NUT: RP11-194H7 covering the gene or BAC 87M17 and YAC 766E7 flanking the gene.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 485 Probes for BRD4: RP11-637P24 covering the gene or BACs 1H8+64O3 and BACs 412E10+3D4 flanking the gene. Variants t(15;?)(q14;?) leading to rearrangement and fusion of NUT to an unknown partner gene. Genes involved and Proteins Gene Name NUT (nuclear protein in testis) Location 15q14 (position 32425358-32437221 on the chromosome 15 genomic sequence according to the UCSC database; assembly of May 2004) Dna / Rna The gene consists of 7 exons that span approximately 12 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon and the stop codon are predicted to exon 1 and exon 7, respectively. The corresponding wildtype mRNA transcript is 3.6 kb. Protein The open reading frame is predicted to encode a 1127 amino acid protein with an estimated molecular weight of 120 kDa. The protein is nuclear and Northern blot analysis has indicated that the normal expression of the NUT gene is highly restricted to the testis.

Gene Name BRD4 (bromodomain containing 4) Location 19p13 (position 15252262-15209302 on the chromosome 19 genomic sequence according to the UCSC database; assembly of May 2004). Dna / Rna The gene consists of 20 exons that span approximately 43 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon and stop codon are located to exon 2 and exon 20, respectively. Two isoforms of BRD4 have been reported. The BRD4 long isoform encodes a 6.0 kb mRNA that corresponds to the full length transcript. The BRD4 short isoform encodes a 4.4 kb mRNA that corresponds to an alternative splicing variant lacking exons 12-20. Protein The open reading frame encodes a 1362 amino acid protein with a molecular weight of 200 kDa. The protein is nuclear and Northern blot analysis has shown an ubiquitous normal expression of both BRD4 isoforms.

Result of the chromosomal anomaly Hybrid Gene Description The t(15;19)(q14;p13) results in a BRD4-NUT chimeric gene where exon 10 of BRD4 is fused to exon 2 of NUT. Detection The hybrid gene can be visualized by FISH using gene specific probes or by RT-PCR. Fusion

Protein Description The BRD4-NUT fusion protein is composed of the N-terminal of BRD4 (amino acids 1- 720 out of 1372) and almost the entire protein sequence of NUT (amino acids 6-1127). The N-terminal of BRD4 includes bromodomains 1 and 2 and other, less well characterized functional domains. Oncogenesis It has been suggested that the oncogenic effect of the NUT-BRD4 fusion is caused not only by the abnormal regulation of NUT by BRD4 promotor elements but also by the consequent ectopic expression of NUT in non-germinal tissues.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 486 Bibliography Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19). Kees UR, Mulcahy MT, Willoughby MLN. Am J Pediatr Hematol Oncol. 1991; 13: 459-464. Medline 1785673

Novel t(15;19) chromosome abnormality in a thymic carcinoma. Kubonishi I, Takehara N, Iwata J, Sonobe H, Ohtsuki Y, Abe T, Miyoshi I. Cancer Res. 1991; 51: 3327-3328. Medline 2040007

Disseminated mediastinal carcinoma with chromosomal translocation (15;19). A distinctive clinicopathologic syndrome. Lee ACW, Kwong Y-I, Fu KH, Chan GCF, Ma L, Lau Y-I. Cancer. 1993; 72: 2273-2276. Medline 8374886

Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD, Roberts JR, Carbone DP. J Natl Cancer Inst. 2000; 92: 1355-1357. Medline 10944559

BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. Am J Pathol. 2001; 159: 1987-1992. Medline 11733348

Upper respiratory tract carcinoma with chromosomal translocation 15;19. Evidence for a distinct disease entity of young patients with a rapidly fatal course. Vargas SO, French CA, Faul PN, Fletcher JA, Davis IJ, Dal Cin P, Perez-Atayde AR. Cancer. 2001; 92: 1195-1203. Medline 11571733

BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. Cancer Res. 2003; 63: 304-307. Medline 12543779

Translocation t(11;15;19): a highly specific chromosome rearrangement associated with poorly differentiated thymic carcinoma in young patients. Toretsky JA, Jenson J, Sun C-C, Eskenazi AE, Campbell A, Hunger SP, Caires A, Frantz C, Hill JL, Stamberg J. Am J Clin Oncol. 2003; 26: 300-306. Medline 12796605

Midline carcinoma of children and young adults with NUT rearrangement. French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, Nose V, Vargas SO, Moschovi M, Tzortzatou-Stathopoulo F, Miyoshi I, Perez-Atayde AR, Aster JC, Fletcher JA. J Clin Oncol. 2004; 22: 4135-4139. Medline 15483023

Carcinoma with t(15;19) translocation. Marx A, French CA, Fletcher JA.

Atlas Genet Cytogenet Oncol Haematol 2007; 3 487 In: World Health Organization classification of tumours. Pathology and genetics of tumours of the lung, thymus, pleura and heart. Travis WD, Brambilla E, Muller-Hermelink K, Harris CC, editors. Oxford University Press 2004. pp. 185-186.

Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. You J, Croyle JL, Nishimura A, Ozato K, Howley P. Cell. 2004; 117: 349-360. Medline 15109495

Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy. Engleson J, Soller M, Panagopoulos I, Dahlen A, Dictor M, Jerkeman M. BMC Cancer. 2006; 6: 69. Medline 16542442

Successful treatment of a child with t(15;19)-positive tumor. Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA. Pediatr Blood Cancer. 2006. Medline 16435379

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 02-2007 Anna Collin Citation This paper should be referenced as such : Collin A . Carcinoma with t(15;19) translocation. Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Tumors/Carcinot1519q14p13ID5474.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 488 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Diamond-Blackfan anemia (DBA)

Identity Inheritance Genetic heterogeneity; majority of cases autosomal dominant, occasionally with variable expression (incomplete dominance) manifesting as mild anemia or only macrocytosis and/or elevated erythrocyte activity (eADA) in transmitting parent or in siblings; some cases apparently autosomal recessive, not linked to 19q Clinics Note Chronic constitutional aregenerative anemia with absent or decreased red cell precursors in bone marrow. Macrocytosis, elevated fetal hemoglobin and increased eADA. Physical abnormalities in about 40% of DBA cases including craniofacial and thumb abnormalities, atrial or ventrucular septal defects, short stature, mild retardation, etc. Hematologic malignancy : in 2.5% of all reported cases of DBA; primarily ANLL with no FAB preference but also ALL, Hodgkin's disease. Solid tumors include carcinoma of liver, stomach, osteogenic sarcoma. Age of malignancy onset from 2 to 43 years. Disease-related and treatment-related factors, i.e., allosensitization and iron overload, contribute to malignancy. Treatment Corticosteroids, transfusion, bone marrow transplant. Evolution Some patients enter remission, with or without corticosteroid therapy. Prognosis Median survival: 38 years Genes involved and Proteins

Gene Name RPS19 Location 19q13.2 Protein Description Ribosomal protein S19; ribosomal proteins are a major component of cellular proteins. In general their function(s), aside from being part of the ribosome, are unknown. However, RPS19 protein was shown to be essential for 18S rRNA maturation and 40S subunit synthesis. Haplo-insufficiency of the protein encoded by the mutated gene is a likely mechanism underlying the pathogenesis of DBA. Mutations Germinal 62 different heterozygous mutations in RPS19 were identified and reported in 113 of the 457 (about 25%) DBA probands. They were non-sense, frameshift, splice site and missense mutations. Several patients had disease-associated chromosomal abnormalities in DBA region, including t(X;19), t(8;19), and 19q microdeletions.

Gene Name RPS24 Location 10q22.3 DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2007; 3 489 Description ribosomal protein S24 Mutations Germinal Three heterozygous mutations in RPS24 (two nonsense and one splice site mutations causing premature termination codons and skipped exon, respectively) were identified among 185 RPS19-negative DBA probands (about 2%).

Bibliography Diamond-Blackfan anemia and malignancy. A case report and review of the literature. Van Dijken PJ, Verwijs W. Cancer 1995; 76: 517-520. REVIEW. Medline 8625135

Diamond-Blackfan anemia. Natural history and sequelae of treatment. Janov AJ, Leong T, Nathan DG, Guinan EC. Medicine. 1996; 75(2): 77-78. Medline 8606629

Identification of microdeletions spanning the Diamond-Blackfan anemia locus (DBA) on 19q13 and evidence for genetic heterogeneity. Gustavsson P, Garelli E, Draptchinskaia N, Ball S, Willig T-N, Tentler D, Dianzani I, Punnett HH, Shafer F, Cario H, Ramenghi U, Glomstein A, Pfeiffer RA, Goringe A, Oliver NF, Smibert E, Tchernia G, Elinder G, Dahl N. Am J Human Genet 1998; 63: 1388-1395. Medline 9792865

The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anemia. Draptchinskaia N, Gustavsson P, Andersson B, Petterson M, Willig TN, Dianzani I, Ball S, Tchernia G, Klar J, Matsson H, Tentler D, Mohandas N, Carlsson B, Dahl N. Nature Genet 1999; 21: 169-174. Medline 9988267

Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression. Willig TN, Draptchinskaia N, Dianzani I, Ball S, Niemeyer C, Ramenghi U, Orfali K, Gustavsson P, Garelli E, Brusco A, Tiemann C, Perignon JL, Bouchier C, Cicchiello L, Dahl N, Mohandas N, Tchernia G. Blood 1999; 94: 4294-4306. Medline 10590074

The Diamond Blackfan Anemia Registry: tool for investigating the epidemiology and biology of Diamond-Blackfan anemia. Vlachos A, Klein GW, Lipton JM. J. Pediatr. Hematol. Oncol. 2001; 23(6): 377-382. Medline 11563775

Ribosomal protein S19 expression during erythroid differentiation. Da Costa L, Narla G, Willig TN, Peters LL, Parra M, Fixler J, Tchernia G, Mohandas N. Blood 2003; 101: 318-324. Medline 12393682

RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with

Atlas Genet Cytogenet Oncol Haematol 2007; 3 490 RPS19 mutations. Gazda HT, Zhong R, Long L, Niewiadomska E, Lipton JM, Ploszynska A, Zaucha JM, Vlachos A, Atsidaftos E, Viskochil DH, Niemeyer CM, Meerpohl JJ, Rokicka-Milewska R, Pospisilova D, Wiktor- Jedrzejczak W, Nathan DG, Beggs AH, Sieff CA. Br J Haematol. 2004; 127: 105-113. Medline 15384984

Diamond Blackfan anaemia in the UK: clinical and genetic heterogeneity. Orfali KA, Ohene-Abuakwa Y, Ball SE. Br J Haematol 2004; 125:243-252. Medline 15059149

An RNA interference model of RPS19 deficiency in Diamond-Blackfan anemia recapitulates defective hematopoiesis and rescue by dexamethasone: identification of dexamethasone- responsive genes by microarray. Ebert BL, Lee MM, Pretz JL, Subramanian A, Mak R, Golub TR, Sieff CA. Blood. 2005; 105(12): 4620-4626. Medline 15755903

Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia. Flygare J, Kiefer T, Miyake K, Utsugisawa T, Hamaguchi I, Da Costa L, Richter J, Davey EJ, Matsson H, Dahl N, Wiznerowicz M, Trono D, Karlsson S. Blood. 2005; 105(12): 4627-4634. Medline 15626736

Two-phase culture in Diamond Blackfan anemia: localization of erythroid defect. Ohene-Abuakwa Y, Orfali KA, Marius C, Ball SE. Blood. 2005; 105(2): 838-846. Medline 15238419

Translational efficiency in patients with Diamond-Blackfan anemia. Cmejlova J, Dolezalova L, Pospisilova D, Petrtylova K, Petrak J, Cmejla R. Haematologica. 2006; 91(11): 1456-1464. Medline 17082006

High-risk pregnancies in Diamond-Blackfan anemia: a survey of 64 pregnancies from the French and German registries. Faivre L, Meerpohl J, Da Costa L, Marie I, Nouvel C, Gnekow A, Bender-Gotze C, Bauters F, Coiffier B, Peaud PY, Rispal P, Berrebi A, Berger C, Flesch M, Sagot P, Varet B, Niemeyer C, Tchernia G, Leblanc T. Haematologica. 2006; 91(4): 530-533. Medline 16537118

Diamond-Blackfan anemia: erythropoiesis lost in translation. Flygare J, Karlsson S. Blood. 2006; Medline 17164339

Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Gazda HT, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton JM, Vlachos A, Atsidaftos E, Ball SE, Orfali KA, Niewiadomska E, Da Costa L, Tchernia G, Niemeyer C, Meerpohl JJ, Stahl J, Schratt G, Glader B, Backer K, Wong C, Nathan DG, Beggs AH, Sieff CA. Am J Hum Genet. 2006; 79(6): 1110-1118. Medline 17186470

Atlas Genet Cytogenet Oncol Haematol 2007; 3 491

Ribosomal Protein Gene Expression Alters Transcription, Translation, Apoptosis, and Oncogenic Pathways in Diamond-Blackfan Anemia. Gazda HT, Kho AT, Sanoudou D, Zaucha JM, Kohane IS, Sieff CA, Beggs AH. Stem Cells. 2006; 24: 2034-2044. Medline 16741228

Analysis of RPS19's interactome. Orru S, Aspesi A, Armiraglio M, Caterino M, Loreni F, Ruoppolo M, Santoro C, Dianzani I. Mol Cell Proteomics. 2006; Medline 17151020

Impaired ribosome biogenesis in Diamond-Blackfan anemia. Choesmel V, Bacqueville D, Rouquette J, Noaillac-Depeyre J, Fribourg S, Cretien A, Leblanc T, Tchernia G, Da Costa L, Gleizes PE. Blood. 2007; 109(3): 1275-1283. Medline 17053056

Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Flygare J, Aspesi A, Bailey JC, Miyake K, Caffrey JM, Karlsson S, Ellis SR. Blood. 2007; 109(3): 980-986. Medline 16990592

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 05-1999 Hope H. Punnett Updated 02-2007 Hanna T. Gazda Citation This paper should be referenced as such : Punnett HH . Diamond-Blackfan anemia (DBA). Atlas Genet Cytogenet Oncol Haematol. May 1999 . URL : http://AtlasGeneticsOncology.org/Kprones/DiamondBlackfanID10040.html Gazda HT . Diamond-Blackfan anemia (DBA). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Kprones/DiamondBlackfanID10040.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 492 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet) t(16;21)(q24;q22) in therapy-related acute myelogenous leukemia arising from myelodysplastic syndrome

Paola Dal Cin, Karim Ouahchi

Clinics Age and sex : 32 yrs old male patient Previous history : preleukaemia RAEB diagnosed in 09-2006+ Hodgkin's lymphoma diagnosed in 2003; Organomegaly : no hepatomegaly; no splenomegaly; enlarged lymph nodes; no central nervous system involvement Blood WBC : 0.29 x 109/l; Hb : 10.7 g/dl; platelets : 19 x 109/l; Bone marrow : Megakaryocytes: none noted; Blasts: 65%; Promyelocytes: 1%; Myeloid Activity: 20%, occasional dysplastic forms; Erythroid Activity: 12%, occasional dysplastic forms; Lymphocytes: 2% Cyto pathology classification Cytology and immunophenotype : M2 arising from previous myelodysplastic syndrome (RAEB-1) Population of immature cells is positive for CD34 +, CD45 (dim), HLA-DR +, CD117 +, CD13 +, and CD33+ and negative for CD15-, monocytic, B and T lymphoid markers. Pathology : Involvement by acute myelogenous leukemia (FAB-M2) with background dysmyelopoiesis. Survival Date of diagnosis: Hodgkin's lymphoma: (2003); myelodysplastic syndrome: (09-2006) karyotype was not performed; therapy-related AML: (01-11-2007) karyotype showing t(16;21) Treatment : Chemotherapy and radiotherapy; chlorambucil, Vinblastine Procarbazine, Prednisone (MOPP) until June 2004; radiotherapy in 2004; ifosfamide, carboplatin and etoposide (ICE) in August 2005; autologous bone marrow transplant in August 2006, and conditioning regimen consisted of Cytoxan, BCNU and etoposide. Induction therapy in January 2007 (16-01-07) and preparation for second transplant. Complete remission was obtained Comments : bone marrow biopsy performed on 03-01-2007 showing no evidence of leukemia and 2% of blast. Karyotype performed on bone marrow aspirate was interpreted as 46, XY in 20 metaphases. Relapse : - Status : Alive 03-2007 Karyotype Sample : Bone marrow aspirate; culture time : 24; banding : GTG Results : 49,XY,+Y,+3,+8,t(16;21)(q24;q22)[18]/46,XY[2] Other molecular cytogenetics technics : FISH evaluation for AML1 rearrangement was performed on abnormal metaphases with the LSI TEL/AML1 ES Dual Color Translocation Probe (Abbott

Atlas Genet Cytogenet Oncol Haematol 2007; 3 493 Molecular/Vysis, Inc.). Other molecular cytogenetics results : Ish der(16)(dimAML1+), der(21)(dimAML1+)[5/5] (see Fig. 2).

Partial GTG-banding karyotype showing t(16;21)(q24;q22)(a) and numerical anomalies. Partial FISH analysis showing the AML1 hybridization signals on the derivative chromosomes 16 and 21 and on the normal chromosome 21(b).

Comments The t(16;21) was reported mostly in t-MDS/t-AML, and classified as M2 in a majority of cases. Two cases including this current report were observed after treatment for Hodgkin lymphoma. Trisomy 8 is a frequent secondary abnormality associated with t(16;21), however in this current case we also report the presence of an additional chromosome Y and trisomy 3. Internal links Atlas Card t(16;21)(q24;q22)

Atlas Genet Cytogenet Oncol Haematol 2007; 3 494 A new case of t(16;21)(q24;q22) in a secondary AML-M2 following breast cancer Case Report therapy Bibliography t(16;21)(q24;q22). Pérot C . Atlas Genet Cytogenet Oncol Haematol 1998; 2 (3): 335-338. http://AtlasGeneticsOncology.org/Anomalies/t1621ID1123.html

A pediatric case of secondary leukemia associated with t(16;21)(q24;q22) exhibiting the chimeric AML1-MTG16 gene. Kondoh K, Nakata Y, Furuta T, Hosoda F, Gamou T, Kurosawa Y, Kinoshita A, Ohki M, Tomita Y, Mori T. Leuk Lymphoma. 2002; 43: 415-420. Medline 11999578 t(16;21)(q24;q22). Huret JL. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (4): 576-578. http://AtlasGeneticsOncology.org/Anomalies/t1621ID1123.html

Abnormalities of the long arm of chromosome 21 in 107 patients with hematopoietic disorders: a collaborative retrospective study of the Groupe Francais de Cytogenetique Hematologique. Jeandidier E, Dastugue N, Mugneret F, Lafage-Pochitaloff M, Mozziconacci MJ, Herens C, Michaux L, Verellen-Dumoulin C, Talmant P, Cornillet-Lefebvre P, Luquet I, Charrin C, Barin C, Collonge-Rame MA, Perot C, Van den Akker J, Gregoire MJ, Jonveaux P, Baranger L, Eclache-Saudreau V, Pages MP, Cabrol C, Terre C, Berger R; Groupe Francais de Cytogenetique Hematologique (GFCH). Cancer Genet Cytogenet. 2006; 166: 1-11. Medline 16616106

Contributor(s) Written 02-2007 Paola Dal Cin, Karim Ouahchi Citation This paper should be referenced as such : Dal Cin P, Ouahchi K . t(16;21)(q24;q22) in therapy-related acute myelogenous leukemia arising from myelodysplastic syndrome. Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Reports/1621DalCinID100022.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 495 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)

A de novo AML with a t(1;21)(p36;q22) in an elderly patient

Paola Dal Cin, Andrew J Yee, Bimalangshu Dey

Clinics Age and sex : 81 yrs old male patient Previous history : no preleukemia ; -no inborn condition of note Organomegaly : no hepatomegaly; no splenomegaly; enlarged lymph nodes; no central nervous system involvement Blood WBC : 3.3 x 109/l; Hb : N/A g/dl; platelets : 16 x 109/l; blasts : 2% (CD34+ myeloblasts) Bone marrow : 20% myeloid precursors, 16% erythroid precursor, 6% lymphocytes, 55% blasts and 2% plama cells. Cyto pathology classification Cytology and immunophenotype : AML M0 CD33+, CD13+, MPO-, CD41-, CD61-, CD203c- (5% of all blast). Rearranged Ig Tcr : N/A Precise diagnosis : Immunophenotype consistent with the presence of myeloid precursors. Negative markers (CD61,CD41,CD203c) associated with megakaryocytic differentiation; AML M0. Survival Date of diagnosis: 01-2005 Treatment : Hydroxyurea and supportive care. Complete remission : None Treatment related death : - Relapse : Patient never achieved complete remission. Status : Dead 02-2005 Survival : 1 Karyotype Sample : Bone marrow; culture time : 24; banding : GTG Results : 46,XY,t(1;21)(p36;q22)[15] Other molecular cytogenetics technics : FISH with LSI (TEL/AML1 ES Dual Color Translocation Probe (Vysis, Inc.) on metaphases (see Fig 2). Other molecular cytogenetics results : Ish der(1)(dimAML1+), der(21)(dimAML1+).

Atlas Genet Cytogenet Oncol Haematol 2007; 3 496

Partial GTG-banding karyotype showing t(1;21)(p36;q22)) (a ) Partial FISH analysis showing the AML1 hybridization signals on derivative chromosomes 1 and 21, and on the normal chromosome 21 (b)

Comments The t(1;21)(p36;q22) so far reported, is generally observed as the sole chromosomal abnormality (5/6), and is mostly a de novo aberration (4/6). The short survival (one month) of our case, confirms the poor prognosis in these patients carrying this chromosome abnormality. Internal links Atlas Card t(1.21)(p36;q22) Bibliography Identification of truncated RUNX1 and RUNX1-PRDM16 fusion transcripts in a case of

Atlas Genet Cytogenet Oncol Haematol 2007; 3 497 t(1;21)(p36;q22)-positive therapy-related AML. Stevens-Kroef MJ, Schoenmakers EF, van Kraaij M, Huys E, Vermeulen S, van der Reijden B, van Kessel AG. Leukemia 2006; 20: 1187-1189. Medline 16598304 t(1;21)(p36;q22) - updated. Marian Stevens-Kroef. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 422-426. http://AtlasGeneticsOncology.org/Anomalies/t0121ID1186.html

Contribution of multiparameter genetic analysis to the detection of genetic alterations in hematologic neoplasia. An evaluation of combining G-band analysis, spectral karyotyping, and multiplex reverse-transcription polymerase chain reaction (multiplex RT-PCR). Preiss BS, Kerndrup GB, Pedersen RK, Hasle H, Pallisgaard N; Lymphoma-Leukemia Study Group of the Region of Southern Denmark. Cancer Genet Cytogenet 2006; 165: 1-8. Medline 16490591

Contributor(s) Written 03-2007 Paola Dal Cin, Andrew J Yee, Bimalangshu Dey Citation This paper should be referenced as such : Dal Cin P, Yee AJ, Dey B . A de novo AML with a t(1;21)(p36;q22) in an elderly patient. Atlas Genet Cytogenet Oncol Haematol. March 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0121DalCinID100021.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 3 498