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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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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 7, Number 2, Apr-Jun 2003 Previous Issue / Next Issue Genes AML1 (acute myeloid leukemia 1); CBFA2; RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)) (21q22.3) - updated. Jean-Loup Huret, Sylvie Senon.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 163-170. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/AML1.html

MAPK8 (mitogen-activated protein kinase 8) (10q11.21).

Fei Chen.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 171-178. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/JNK1ID196.html

MAPK9 (mitogen-activated protein kinase 9) (5q35).

Fei Chen.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 179-184. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/JNK2ID426.html

MAPK10 (mitogen-activated protein kinase 10) (4q21-q23).

Fei Chen.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 185-190. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2003; 2 I URL : http://AtlasGeneticsOncology.org/Genes/JNK3ID427.html

JUNB (19p13.2).

Fei Chen.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 191-195. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/JUNBID178.html

JUN-D proto-oncogene (19p13.1-p12).

Fei Chen.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 196-200. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/JUNDID179.html

JUN (V-Jun sarcoma virus 17 oncogene homolog (avian)) (1p32-p31).

Fei Chen.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 201-206. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/JUNID151.html

RECQL (12p12-p11).

Mounira Amor-Guéret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 207-210. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/RECQLID283.html

BCL9 (B-cell CLL/lymphoma 9) (1q21).

Jean-Loup Huret, Sylvie Senon.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 211-213. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/BCL9ID466.html

WFDC1 (WAP four-disulfide core domain 1) (16q24.1).

Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 214-219. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/WFDC1ID424.html

ELL (eleven nineteen lysin rich leukemia gene) (19p13.1) - updated.

Jay L Hess.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 II Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 220-224. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/ELL.html Leukaemias

t(7;9)(q34;q34).

Jacques Boyer.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 225-228. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0709q34q34ID1055.html

t(7;19)(q34;p13).

Jacques Boyer.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 229-232. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0719q34p13ID1060.html

3q rearrangements in myeloid malignancies.

Bruce Poppe, Nicole Dastugue, Frank Speleman.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 233-238. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/3qrearrmyeloID1125.html

t(2;21)(p11;q22).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 239-240. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0221p11q22ID1261.html

t(4;21)(q31;q22).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 241-242. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0421q31q22ID1262.html

t(5;21)(q13;q22).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 243-244. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0521q13q22ID1174.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 III t(6;21)(p22;q22).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 245-246. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0621p22q22ID1266.html

t(8;21)(q24;q22).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 247-248. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0821q24q22ID1263.html

t(12;21)(q24;q22).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 249-250. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t1221q24q22ID1268.html

t(14;21)(q22;q22).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 251-252. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t1421q22q22ID1269.html

t(15;21)(q22;q22).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 253-254. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t1521q22q22ID1270.html

t(20;21)(q13;q22).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 255-256. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t2021q13q22ID1264.html Solid Tumours

Bone: Adamantinoma.

Hans Marten Hazelbag, Pancras CW Hogendoorn.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 IV Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 257-262. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Tumors/AdamantinID5154.html

Neuroendocrine tumors: Phaeochromocytoma.

Anne-Paule Gimenez-Roqueplo.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 263-270. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Tumors/pheochromocytomaID5026.html

Soft tissue tumors: an overview.

Paola Dal Cin.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 271-283. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Tumors/softissuTumID5042.html Cancer Prone Diseases Deep Insights

Heterochromatin, from Chromosome to Protein.

Marie-Geneviève Mattei and Judith Luciani.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 284-299. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Deep/HeterochromatineDEEP.html

The WNT Signaling Pathway and Its Role in Human Solid Tumors.

Lin Thorstensen, Ragnhild A. Lothe.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 300-331. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Deep/WNTSignPathID20042.html Case Reports Educational Items

Transcription factors.

Valentina Guasconi, Hakima Yahi, Slimane Ait-Si-Ali.

Atlas Genet Cytogenet Oncol Haematol 2003; 7 (2): 332-336. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Educ/TFactorsEng.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 V

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Atlas Genet Cytogenet Oncol Haematol 2003; 2 VI Atlas of Genetics and Cytogenetics in Oncology and Haematology

AML1 (acute myeloid leukemia 1) (updated: old version not available) RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)) CBFA2 (core binding factor A2)

Identity Other PEBPaB (polyomavirus enhancer binding protein aB) names Hugo RUNX1 Location 21q22.3

AML1 (21q22.3) in normal cells: clone dJ1107L6 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are wellcome: contact M Rocchi

DNA/RNA

DNA Diagram

Description the gene spans a region of more than 120 kb Transcription transcription is from telomere to centromere --> the fusion gene is located on the 'other' chromosome (eg the der(8) of the t(8;21), the der(3) of the t(3;21)...); alternate splicing --> transcripts of 2, 3.3, ->7.5 and 8 kb Protein

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -163-

Protein Diagram

Description 250, 453 amino acids and other forms; forms heterodimers with CBFB Expression widely expressed, including hematopoietic cells at various stages of differenciation: role in haematopoiesis Localisation nuclear Function transcription factor (activator) for various hematopoietic-specific genes: binds to the core site 5' PyGPyGGTPy 3' of a number of promotors and enhancers, as in GM-CSF (granulocyte-macrophage colony stimulating factor, CSF1R (colony stimulating factor 1 receptor), TCRb sites (T cell antigen receptors), and myeloid myeloperoxidase Homology 1- Runt (drosophila): nuclear DNA binding protein; role in segmentation (embryology); 2- AML2 (also called: CBFA3, CBFa3, PEBPaC), located in 1p35-36, expressed in B lineage (3 and 5 kb RNA); AML3: (also called: CBFA1, CBFa1, PEBPaA) in 6p21; 3- cbfa family (mouse) Implicated in Entity Familial platelet disorder with predisposition to acute non lymphocytic leukemia

Entity t(1;21)(p36;q22) treatment related acute non lymphocytic leukemia (ANLL) --> ?/ AML1

Entity t(2;21)(p11;q22) ANLL --> ?/ AML1

Entity t(3;21)(q26;q22)/ myelodysplastic syndrome (MDS) or ANLL --> - EVI1 or EAP/ MDS1 - AML1 Disease CML-BC of myeloid type; ANLL and MDS, often therapy related (secondary to antitopoisomerase II) Hybrid/Mutated 5' AML1 - 3' EAP or MDS1 or EVI1 Gene

Entity t(4;21)(q31;q22) T-cell acute lymphoblastic leukemia (T-ALL) --> ?/ AML1

Entity t(5;21)(q13;q22) myelodysplastic syndrome (MDS) and ANLL --> ?/ AML1

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -164-

Entity t(8;21)(q22;q22)/ANLL. --> ETO - AML1 Disease ANLL, M2 mostly Prognosis CR is obtained; median survival (1.5-2 yrs) is the range with other ANLL or relatively better Cytogenetics additional anomalies are frequent: loss of Y or X chromosome, del(7q)/-7, +8, del (9q); complex t(8;21;Var) are known and have revealed that the crucial event lies on der(8); in agrement with the fact that both genes are transcribed from telomere to centromere Hybrid/Mutated 5' AML1 - 3' ETO Gene Abnormal N-term AML1 with the Runt domain fused to the nearly entire ETO Protein Oncogenesis the fusion protein retain the ability to recognize the AML1 concensus binding site (--> negative dominant competitor with the normal AML1) and to dimerize with the cbtb/CBTB subunit --> probable altered transcriptional regulation of normal AML1 target genes

Entity t(8;21)(q23;q22) MDS --> FOG2 / AML1

Entity t(8;21)(q24;q22) ALL and ANLL --> TRPS1 / AML1

Entity t(12;21)(p13;q22)/ALL --> ETV6-AML1 Disease B cell ALL (CD10+) Prognosis CR in all cases; prognosis seems good Cytogenetics often undetectable without FISH; additional anomalies: frequent del(12)(p12) on the other allele Hybrid/Mutated 5' ETV6 - 3' AML1on the der(21) Gene Abnormal Helix loop helix of TEL fused to the nearly entire AML1 protein; the Protein other TEL allele is often deleted

Entity t(12;21)(q24;q22) ANLL --> ?/ AML1

Entity t(16;21)(q24;q22) ANLL --> MTG16-AML1 Disease ANLL and therapy related ANLL; mainly with preceeding MDS Prognosis very poor

Entity t(17;21)(q11;q22) ANLL

Entity t(19;21)(q13;q22) treatment related ANLL --> AMP19 / AML1

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -165-

Entity t(20;21)(q1;3q22) treatment related ANL --> ? / AML1

Entity t(21;21)(q11;q22) MDS --> UPS25 / AML1

Breakpoints

External links Nomenclature Hugo RUNX1 GDB RUNX1 RUNX1 861 runt-related transcription factor 1 (acute myeloid Entrez_Gene leukemia 1; aml1 oncogene) Cards Atlas FGA7ID525 GeneCards RUNX1 Ensembl RUNX1 CancerGene CBFA2 Genatlas RUNX1

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -166- GeneLynx RUNX1 eGenome RUNX1 euGene 861 Genomic and cartography RUNX1 - 21q22.3 chr21:35081969-35182857 - 21q22.12 (hg17- GoldenPath May_2004) Ensembl RUNX1 - 21q22.12 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RUNX1 Gene and transcription

Genbank AF025841 [ SRS ] AF025841 [ ENTREZ ]

Genbank AJ229043 [ SRS ] AJ229043 [ ENTREZ ]

Genbank AA878154 [ SRS ] AA878154 [ ENTREZ ]

Genbank AK123035 [ SRS ] AK123035 [ ENTREZ ]

Genbank AL581043 [ SRS ] AL581043 [ ENTREZ ]

RefSeq NM_001001890 [ SRS ] NM_001001890 [ ENTREZ ]

RefSeq NM_001754 [ SRS ] NM_001754 [ ENTREZ ]

RefSeq NT_086913 [ SRS ] NT_086913 [ ENTREZ ] AceView RUNX1 AceView - NCBI TRASER RUNX1 Traser - Stanford

Unigene Hs.278446 [ SRS ] Hs.278446 [ NCBI ] HS278446 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q01196 [ SRS] Q01196 [ EXPASY ] Q01196 [ INTERPRO ] CluSTr Q01196 Blocks Q01196 Polymorphism : SNP, mutations, diseases OMIM 151385 [ map ] GENECLINICS 151385

SNP RUNX1 [dbSNP-NCBI]

SNP NM_001001890 [SNP-NCI]

SNP NM_001754 [SNP-NCI]

SNP RUNX1 [GeneSNPs - Utah] RUNX1 [SNP - CSHL] RUNX1] [HGBASE - SRS] General knowledge Family RUNX1 [UCSC Family Browser] Browser SOURCE NM_001001890 SOURCE NM_001754

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -167- SMD Hs.278446 SAGE Hs.278446 Amigo function|ATP binding Amigo process|development Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity PubGene RUNX1 Other databases Probes Probe AML1 (21q22.3) in normal cells (Bari) Probe RUNX1 Related clones (RZPD - Berlin) PubMed PubMed 65 Pubmed reference(s) in LocusLink Bibliography Molecular basis of the t(8;21) translocation in acute myeloid leukaemia. Ohki M. Semin Cancer Biol. 1993 Dec;4(6):369-75. Review. Medline 94191184

AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Nucifora G, Rowley JD Blood. 1995 Jul 1;86(1):1-14. Review. Medline 95315523.

High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Romana SP, et al. Blood. 1995 Dec 1;86(11):4263-9. Medline 7492786

CBFA2(AML1) Translocations With Novel Partner Chromosomes in Myeloid Leukemias: Association With Prior Therapy. Roulston D, Espinosa IIIR, Nucifora G, Larson RA, Le Beau MM, Rowley JD. Blood 1998; 92: 2879-2885.

Combined spectral karyotyping and DAPI banding analysis of chromosome abnormalities in myelodysplastic syndrome. Kakazu N, Taniwaki M, Horiike S, Nishida K, Tatekawa T, Nagai M, Takahashi T, Akaogi T, Inazawa J, Ohki M, Abe T. Genes Chromosomes Cancer 1999; 26: 336-345.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -168- Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, Maris JM, Gilliland DG. Nat Genet. 1999;23:134-135.

Concurrent translocations of MLL and CBFA2 (AML1) genes with new partner breakpoints in a child with secondary myelodysplastic syndrome after treatment of acute lymphoblastic leukemia. Mathew S, Head D, Rubnitz JE, Raimondi SC. Genes Chromosomes Cancer 2000; 28: 227-232. Medline 10825008

Identification of two new translocations that disrupt the AML1 gene. Richkind K, Hromas R, Lytle C, Crenshaw D, Velasco J, Roherty S, Srinivasiah J, Varella-Garcia M. Cancer Genet Cytogenet 2000; 122: 141-143.

A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations Hromas R, Shopnick R, Jumean HG, Bowers C, Varella-Garcia M, Richkind K. Blood 2000; 95:4011-4013

A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies. Buijs A, Poddighe P, van Wijk R, van Solinge W, Borst E, Verdonck L, Hagenbeek A, Pearson P, Lokhorst H. Blood 2001; 98:2856-2858.

Novel cryptic, complex rearrangements involving ETV6-CBFA2 (TEL-AML1) genes identified by fluorescence in situ hybridization in pediatric patients with acute lymphoblastic leukemia. Mathew S, Shurtleff SA, Raimondi SC. Genes Chromosomes Cancer. 2001; 32: 188-193. Medline 11550288

AML1-TRPS1 chimeric protein is generated by t(8;21)(q24;q22) in relapsing acute myeloblastic leukemia. Asou N, Matsuno N, Mitsuya H. Am Soc Hematol, 43 Annual meeting, Blood 2001; 98 11: 564a.

In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, Shigesada K, Ito Y,

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -169- Benson KF, Raskind WH, Rossier C, Antonarakis SE, Israels S, McNicol A, Weiss H, Horwitz M, Scott HS. Blood 2002;99:1364-1372.

A new translocation that rearranges the AML1 gene in a patient with T-cell acute lymphoblastic leukemia. Mikhail FM, Serry KA, Hatem N, Mourad ZI, Farawela HM, El Kaffash DM, Coignet L, Nucifora G. Cancer Genet Cytogenet 2002; 135: 96-100.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 11- Jean-Loup Huret 1997 Updated 12- Jean-Loup Huret 1997 Updated 01- Jean-Loup Huret and Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL . AML1 (acute myeloid leukemia 1); RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)); CBFA2 (core binding factor A2). Atlas Genet Cytogenet Oncol Haematol. November 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/AML1.html Huret JL . AML1 (acute myeloid leukemia 1); RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)); CBFA2 (core binding factor A2). Atlas Genet Cytogenet Oncol Haematol. December 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/AML1.html Huret JL, Senon S . AML1 (acute myeloid leukemia 1); RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)); CBFA2 (core binding factor A2). Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/AML1.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -170- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MAPK8 (mitogen-activated protein kinase 8)

Identity Other JNK1 (C-Jun N-terminal kinase 1) names Stress-activated protein kinase 1 (SAPK1) Hugo MAPK8 Location 10q11.21 DNA/RNA

Description The JNK1 gene maps on chromosome 10q11.21 spanning 130089bp. It contains 22 c 20 of which are alternative. Transcription By alternative splicing, JNK1 gene encodes 13 different transcripts that translate to 13 The predicted molecular weight of JNK1 protein is 44.2 kD. Protein

Description All JNK proteins contain a protein kinase domain that belong to a very extensive family of eukaryotic serine/threonine proteins kinase. A

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -171- number of conserved regions have been identified in the catalytic domain of JNKs. In the N-terminal extremity of the catalytic domain there is a glycine-rich motif in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. A conserved aspartic acid reside that is critical for the catalytic activity of kinase has also been identified in the central part of the catalytic domain. Expression JNK1 is ubiquitously expressed. Localisation Cytoplasmic and nuclear Function The members of JNK family act as an integration point for multiple intracellular biochemical signals governing a wide variety of cellular processes such as proliferation, differentiation, apoptosis, migration, transcriptional regulation, and development JNK targets specific transcription factors and thus mediates immediate-early gene expression in response to various stress signals including ultraviolet (UV) radiation, oxidative stress, protein malfolding in endoplasmic reticulum, osmotical shock, and inflammatory mediators. These transcription factors include AP-1, ATF-2, Elk-1, p53, etc... Several upstream dual specific protein kinases, such as MKK4/SEK1 and MKK7, can activate JNK through phosphorylation of the conversed Thr- Pro-Tyr motif on JNK proteins. In mammalian cells, activated JNK can phosphorylate the N-terminus of c-Jun, which contains both JNK docking site and JNK phosphorylation site (ser63 and ser73), orJunD, which lacks a JNK docking site but contains a JNK phosphorylation site. JNK is unable to phosphorylate JunB due to the lack of a JNK phosphorylation site inJunB, despite there is a functional JNK docking site. Comparison of the binding activity of JNK isoforms demonstrates that JNK2 bind c-Jun approximately 25 times more efficiently than did JNK1. Therefore, individual members of the JNK family may selectively target specific transcription factors in vivo. One of the most important functions of JNK is the regulation of apoptosis. Emerging evidence indicates that JNK activation is obligatory for apoptosis induced by both receptor-mediated ÒextrinsicÓ pathway or mitochondria-mediated ÒintrinsicÓ pathway. JNK activation may contribute to the initiation of Fas-induced apoptosis, possibly through the amplification of autocrine or paracrine Fas signaling by JNK-dependent Fas ligand (FasL) gene expression. In addition, JNK has been indicated in the apoptosis induced by Daxx, a Fas death domain (FADD) interaction protein. Through its serine/threonine kinase activity, JNK may contribute to mitochondria-mediated apoptosis by phosphorylating pro- or anti- apoptoticBcl-2 family proteins. Finally, JNK has also been indicated as an important kinase phosphorylating p53 and subsequently facilitating p53-dependent apoptotic responses. Sustained JNK activation may be responsible for the enhanced apoptosis observed in RelA-/- or Ikkb-/- mouse embryonic fibroblasts treated with TNFa. It was suggested that deficiency of RelA or IKKb caused a decreased expression of XIAP or GADD45b, which may antagonize the activation of JNK activation. However, such speculation contradicts the previous observations indicating that both GADD45b and XIAP are activators, rather than inhibitors for JNK activation. Moreover, gene profiling in our recent

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -172- studies indicated no substantial difference of basal or inducible GADD45b and XIAP mRNA in wild type cells and Ikkb-/- cells. Implicated in Entity Obesity, insulin resistance, neurodegenerative diseases, inflammation, cancer.

External links Nomenclature Hugo MAPK8 GDB MAPK8 Entrez_Gene MAPK8 5599 mitogen-activated protein kinase 8 Cards Atlas JNK1ID196 GeneCards MAPK8 Ensembl MAPK8 CancerGene MAPK8 Genatlas MAPK8 GeneLynx MAPK8 eGenome MAPK8 euGene 5599 Genomic and cartography MAPK8 - 10q11.21 chr10:49279693-49313189 + 10q11.22 GoldenPath (hg17-May_2004) Ensembl MAPK8 - 10q11.22 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MAPK8 Gene and transcription

Genbank AL137667 [ SRS ] AL137667 [ ENTREZ ]

Genbank L26318 [ SRS ] L26318 [ ENTREZ ]

Genbank U34822 [ SRS ] U34822 [ ENTREZ ]

Genbank U35004 [ SRS ] U35004 [ ENTREZ ]

Genbank U35005 [ SRS ] U35005 [ ENTREZ ]

RefSeq NM_002750 [ SRS ] NM_002750 [ ENTREZ ]

RefSeq NM_139046 [ SRS ] NM_139046 [ ENTREZ ]

RefSeq NM_139047 [ SRS ] NM_139047 [ ENTREZ ]

RefSeq NM_139049 [ SRS ] NM_139049 [ ENTREZ ]

RefSeq NT_086769 [ SRS ] NT_086769 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -173- AceView MAPK8 AceView - NCBI TRASER MAPK8 Traser - Stanford

Unigene Hs.522924 [ SRS ] Hs.522924 [ NCBI ] HS522924 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P45983 [ SRS] P45983 [ EXPASY ] P45983 [ INTERPRO ]

Prosite PS01351 MAPK [ SRS ] PS01351 MAPK [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 Prosite PROTEIN_KINASE_ST [ Expasy ]

Interpro IPR008351 JNK_MAPK [ SRS ] IPR008351 JNK_MAPK [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR003527 MAP_kin [ SRS ] IPR003527 MAP_kin [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ]

Interpro IPR002290 Ser_thr_pkinase [ SRS ] IPR002290 Ser_thr_pkinase [ EBI ] CluSTr P45983 Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00220 S_TKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom P45983 MK08_HUMAN [ Domain structure ] P45983 MK08_HUMAN [ sequences sharing at least 1 domain ] Blocks P45983 Polymorphism : SNP, mutations, diseases OMIM 601158 [ map ] GENECLINICS 601158

SNP MAPK8 [dbSNP-NCBI]

SNP NM_002750 [SNP-NCI]

SNP NM_139046 [SNP-NCI]

SNP NM_139047 [SNP-NCI]

SNP NM_139049 [SNP-NCI]

SNP MAPK8 [GeneSNPs - Utah] MAPK8 [SNP - CSHL] MAPK8] [HGBASE - SRS] General knowledge Family MAPK8 [UCSC Family Browser] Browser SOURCE NM_002750

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -174- SOURCE NM_139046 SOURCE NM_139047 SOURCE NM_139049 SMD Hs.522924 SAGE Hs.522924 Enzyme 2.7.1.37 [ Enzyme-SRS ] 2.7.1.37 [ Brenda-SRS ] 2.7.1.37 [ KEGG ] 2.7.1.37 [ WIT ] Amigo function|ATP binding Amigo process|JNK cascade Amigo function|JUN kinase activity Amigo function|MAP kinase activity Amigo process|cell motility Amigo process|protein amino acid phosphorylation Amigo function|protein serine/threonine kinase activity Amigo process|response to stress Amigo process|signal transduction Amigo function|transferase activity BIOCARTA The 4-1BB-dependent immune response Angiotensin II mediated activation of JNK Pathway via Pyk2 BIOCARTA dependent signaling BIOCARTA Pertussis toxin-insensitive CCR5 Signaling in Macrophage BIOCARTA HIV-I Nef: negative effector of Fas and TNF BIOCARTA IL12 and Stat4 Dependent Signaling Pathway in Th1 Development BIOCARTA Agrin in Postsynaptic Differentiation BIOCARTA Oxidative Stress Induced Gene Expression Via Nrf2 BIOCARTA ATM Signaling Pathway BIOCARTA BCR Signaling Pathway BIOCARTA Bioactive Peptide Induced Signaling Pathway BIOCARTA Ceramide Signaling Pathway Regulation of MAP Kinase Pathways Through Dual Specificity BIOCARTA Phosphatases BIOCARTA EGF Signaling Pathway BIOCARTA EPO Signaling Pathway BIOCARTA FAS signaling pathway ( CD95 ) BIOCARTA Fc Epsilon Receptor I Signaling in Mast Cells BIOCARTA Inhibition of Cellular Proliferation by Gleevec BIOCARTA IGF-1 Signaling Pathway BIOCARTA Signal transduction through IL1R BIOCARTA IL 2 signaling pathway

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -175- BIOCARTA Insulin Signaling Pathway BIOCARTA Integrin Signaling Pathway BIOCARTA Keratinocyte Differentiation BIOCARTA Role of MAL in Rho-Mediated Activation of SRF BIOCARTA MAPKinase Signaling Pathway BIOCARTA Signaling of Hepatocyte Growth Factor Receptor NFAT and Hypertrophy of the heart (Transcription in the broken BIOCARTA heart) BIOCARTA Nerve growth factor pathway (NGF) BIOCARTA Hypoxia and p53 in the Cardiovascular system BIOCARTA PDGF Signaling Pathway BIOCARTA Links between Pyk2 and Map Kinases BIOCARTA Bone Remodelling BIOCARTA TNF/Stress Related Signaling BIOCARTA TACI and BCMA stimulation of B cell immune responses. BIOCARTA T Cell Receptor Signaling Pathway BIOCARTA TNFR1 Signaling Pathway BIOCARTA Toll-Like Receptor Pathway PubGene MAPK8 Other databases Probes Probe MAPK8 Related clones (RZPD - Berlin) PubMed PubMed 66 Pubmed reference(s) in LocusLink Bibliography Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Yang X, Khosravi-Far R, Chang HY, Baltimore D. Cell1997; 89: 1067-1076. Medline 9215629

Stress-induced Fas ligand expression in T cells is mediated through a MEK kinase 1-regulated response element in the Fas ligand promoter. Faris M, Latinis KM, Kempiak SJ, Koretzky GA, Nel A. Mol Cell Biol 1998; 18: 5414-5424. Medline 9710625

JNK targets p53 ubiquitination and degradation in nonstressed cells. Fuchs SY, Adler V, Buschmann T, Yin Z, Wu X, Jones SN, Ronai Z. Genes Dev 1998; 12: 2658-2663. Medline 9732264

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -176-

A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Takekawa M, Saito H. Cell 1998; 95: 521-530. Medline 9827804

Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Jacobs D, Glossip D, Xing H, Muslin AJ, Kornfeld K. Genes Dev 1999; 13: 163-175. Medline 9925641

Signal transduction by the JNK group of MAP kinases. Davis RJ Cell 2000; 103: 239-252. Medline 11057897

Induction of gadd45 beta by NF-kappaB downregulates pro-apoptotic JNK signalling. De Smaele E, Zazzeroni F, Papa S, Nguyen DU, Jin R, Jones J, Cong R, Franzoso G. Nature 2001; 414: 308-313. Medline 11713530

Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its antiapoptotic effect in Fas-induced cell death. Suzuki Y, Nakabayashi Y, Takahashi R. Proc Natl Acad Sci U S A 2001; 98: 8662-8667. Medline 11447297

Inhibition of JNK activation through NF-kappaB target genes. Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M, Lin A. Nature 2001; 414: 313-317. Medline 11713531

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

BiblioGene - INIST

Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -177- Written 01- Fei Chen 2003

Citation This paper should be referenced as such : Chen F . MAPK8 (mitogen-activated protein kinase 8). Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/JNK1ID196.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -178- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MAPK9 (mitogen-activated protein kinase 9)

Identity Other JNK2 (C-Jun N-terminal kinase 2) names Stress-activated protein kinase 2 (SAPK2) Hugo MAPK9 Location 5q35 DNA/RNA Description The JNK2 gene maps on chromosome 5q35 spanning 58494bp. It contains 17 confirmed introns, 14 of which are alternative. Transcription By alternative splicing, JNK2 gene encodes 12 types of transcripts that translate to 12 distinct JNK2 isoforms. The molecular weight of JNK2 is about 55 kD. Protein

Description All JNK proteins contain a protein kinase domain that belong to a very extensive family of eukaryotic serine/threonine proteins kinase. A number of conserved regions have been identified in the catalytic domain of JNKs. In the N-terminal extremity of the catalytic domain there is a glycine-rich motif in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. A conserved aspartic acid reside that is critical for the catalytic activity of kinase has also been identified in the central part of the catalytic domain. Expression JNK1 is ubiquitously expressed. Localisation Cytoplasmic and nuclear Function The members of JNK family act as an integration point for multiple intracellular biochemical signals governing a wide variety of cellular processes such as proliferation, differentiation, apoptosis, migration, transcriptional regulation, and development. JNK targets specific transcription factors and thus mediates immediate-early gene expression in response to various stress signals including ultraviolet (UV) radiation, oxidative stress, protein malfolding in endoplasmic reticulum, osmotical shock, and inflammatory mediators. These transcription factors include AP-1, ATF-2, Elk-1, p53, etc... Several upstream dual specific protein kinases, such as MKK4/SEK1 and MKK7, can activate JNK through phosphorylation of the conversed Thr- Pro-Tyr motif on JNK proteins. In mammalian cells, activated JNK can phosphorylate the N-terminus of c-Jun, which contains both JNK

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -179- docking site and JNK phosphorylation site (ser63 and ser73), orJunD, which lacks a JNK docking site but contains a JNK phosphorylation site. JNK is unable to phosphorylate JunB due to the lack of a JNK phosphorylation site inJunB, despite there is a functional JNK docking site. Comparison of the binding activity of JNK isoforms demonstrates that JNK2 bind c-Jun approximately 25 times more efficiently than did JNK1. Therefore, individual members of the JNK family may selectively target specific transcription factors in vivo. One of the most important functions of JNK is the regulation of apoptosis. Emerging evidence indicates that JNK activation is obligatory for apoptosis induced by both receptor-mediated ÒextrinsicÓ pathway or mitochondria-mediated ÒintrinsicÓ pathway. JNK activation may contribute to the initiation of Fas-induced apoptosis, possibly through the amplification of autocrine or paracrine Fas signaling by JNK-dependent Fas ligand (FasL) gene expression. In addition, JNK has been indicated in the apoptosis induced by Daxx, a Fas death domain (FADD) interaction protein. Through its serine/threonine kinase activity, JNK may contribute to mitochondria-mediated apoptosis by phosphorylating pro- or anti- apoptoticBcl-2 family proteins. Finally, JNK has also been indicated as an important kinase phosphorylating p53 and subsequently facilitating p53-dependent apoptotic responses. Sustained JNK activation may be responsible for the enhanced apoptosis observed in RelA-/- or Ikkb-/- mouse embryonic fibroblasts treated with TNFa. It was suggested that deficiency of RelA or IKKb caused a decreased expression of XIAP or GADD45b, which may antagonize the activation of JNK activation. However, such speculation contradicts the previous observations indicating that both GADD45b and XIAP are activators, rather than inhibitors for JNK activation. Moreover, gene profiling in our recent studies indicated no substantial difference of basal or inducible GADD45b and XIAP mRNA in wild type cells and Ikkb-/- cells. Implicated in Entity Obesity, insulin resistance, neurodegenerative diseases, inflammation, cancer.

External links Nomenclature Hugo MAPK9 GDB MAPK9 Entrez_Gene MAPK9 5601 mitogen-activated protein kinase 9 Cards Atlas JNK2ID426 GeneCards MAPK9 Ensembl MAPK9 CancerGene MAPK9 Genatlas MAPK9

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -180- GeneLynx MAPK9 eGenome MAPK9 euGene 5601 Genomic and cartography MAPK9 - 5q35 chr5:179595390-179640216 - 5q35.3 (hg17- GoldenPath May_2004) Ensembl MAPK9 - 5q35.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MAPK9 Gene and transcription

Genbank BC032539 [ SRS ] BC032539 [ ENTREZ ]

Genbank BQ025589 [ SRS ] BQ025589 [ ENTREZ ]

Genbank CR536580 [ SRS ] CR536580 [ ENTREZ ]

Genbank L31951 [ SRS ] L31951 [ ENTREZ ]

Genbank U09759 [ SRS ] U09759 [ ENTREZ ]

RefSeq NM_002752 [ SRS ] NM_002752 [ ENTREZ ]

RefSeq NM_139068 [ SRS ] NM_139068 [ ENTREZ ]

RefSeq NM_139069 [ SRS ] NM_139069 [ ENTREZ ]

RefSeq NM_139070 [ SRS ] NM_139070 [ ENTREZ ]

RefSeq NT_086684 [ SRS ] NT_086684 [ ENTREZ ] AceView MAPK9 AceView - NCBI TRASER MAPK9 Traser - Stanford

Unigene Hs.484371 [ SRS ] Hs.484371 [ NCBI ] HS484371 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P45984 [ SRS] P45984 [ EXPASY ] P45984 [ INTERPRO ]

Prosite PS01351 MAPK [ SRS ] PS01351 MAPK [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 Prosite PROTEIN_KINASE_ST [ Expasy ]

Interpro IPR008351 JNK_MAPK [ SRS ] IPR008351 JNK_MAPK [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR003527 MAP_kin [ SRS ] IPR003527 MAP_kin [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -181- Interpro IPR002290 Ser_thr_pkinase [ SRS ] IPR002290 Ser_thr_pkinase [ EBI ] CluSTr P45984 Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00220 S_TKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom P45984 MK09_HUMAN [ Domain structure ] P45984 MK09_HUMAN [ sequences sharing at least 1 domain ] Blocks P45984 Polymorphism : SNP, mutations, diseases OMIM 602896 [ map ] GENECLINICS 602896

SNP MAPK9 [dbSNP-NCBI]

SNP NM_002752 [SNP-NCI]

SNP NM_139068 [SNP-NCI]

SNP NM_139069 [SNP-NCI]

SNP NM_139070 [SNP-NCI]

SNP MAPK9 [GeneSNPs - Utah] MAPK9 [SNP - CSHL] MAPK9] [HGBASE - SRS] General knowledge Family MAPK9 [UCSC Family Browser] Browser SOURCE NM_002752 SOURCE NM_139068 SOURCE NM_139069 SOURCE NM_139070 SMD Hs.484371 SAGE Hs.484371 Enzyme 2.7.1.37 [ Enzyme-SRS ] 2.7.1.37 [ Brenda-SRS ] 2.7.1.37 [ KEGG ] 2.7.1.37 [ WIT ] Amigo function|ATP binding Amigo process|JNK cascade Amigo function|JUN kinase activity Amigo function|MAP kinase activity Amigo process|protein amino acid phosphorylation Amigo function|protein binding Amigo function|protein serine/threonine kinase activity Amigo process|response to stress Amigo function|transferase activity BIOCARTA MAPKinase Signaling Pathway PubGene MAPK9

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -182- Other databases Probes Probe MAPK9 Related clones (RZPD - Berlin) PubMed PubMed 19 Pubmed reference(s) in LocusLink Bibliography JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Kallunki T, Su B, Tsigelny I, Sluss HK, Derijard B, Moore G, Davis R, Karin M. Genes Dev 1994; 8: 2996-3007. Medline 8001819

Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Yang X, Khosravi-Far R, Chang HY, Baltimore D. Cell1997; 89: 1067-1076. Medline 9215629

JNK targets p53 ubiquitination and degradation in nonstressed cells. Fuchs SY, Adler V, Buschmann T, Yin Z, Wu X, Jones SN, Ronai Z. Genes Dev 1998; 12: 2658-2663. Medline 9732264

A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Takekawa M, Saito H. Cell 1998; 95: 521-530. Medline 9827804

Signal transduction by the JNK group of MAP kinases. Davis RJ Cell 2000; 103: 239-252. Medline 11057897

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -183-

Inhibition of JNK activation through NF-kappaB target genes. Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M, Lin A. Nature 2001; 414: 313-317. Medline 11713531

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Fei Chen 2003 Citation This paper should be referenced as such : Chen F . MAPK9 (mitogen-activated protein kinase 9). Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/JNK2ID426.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -184- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MAPK10 (mitogen-activated protein kinase 10)

Identity Other JNK3 (C-Jun N-terminal kinase 3) names Stress-activated protein kinase 3 (SAPK3) Hugo MAPK10 Location 4q21-q23 DNA/RNA Description The JNK3 gene maps on chromosome 4q22.1-q23 spanning 143716bp. It contains 19 confirmed introns, 16 of which are alternative. Transcription Through alternative splicing, 7 types of transcripts are generated which produce 7 distinct JNK3 proteins. Due to the alternative splicing, the molecular weight of JNK3 varied from 45 to 57 kD. Protein

Description All JNK proteins contain a protein kinase domain that belong to a very extensive family of eukaryotic serine/threonine proteins kinase. A number of conserved regions have been identified in the catalytic domain of JNKs. In the N-terminal extremity of the catalytic domain there is a glycine-rich motif in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. A conserved aspartic acid reside that is critical for the catalytic activity of kinase has also been identified in the central part of the catalytic domain. Expression JNK3 is mainly expressed in nervous system, heart and testis. Function The members of JNK family act as an integration point for multiple intracellular biochemical signals governing a wide variety of cellular processes such as proliferation, differentiation, apoptosis, migration, transcriptional regulation, and development. JNK targets specific transcription factors and thus mediates immediate-early gene expression in response to various stress signals including ultraviolet (UV) radiation, oxidative stress, protein malfolding in endoplasmic reticulum, osmotical shock, and inflammatory mediators. These transcription factors include AP-1, ATF-2, Elk-1, p53, etc... Several upstream dual specific protein kinases, such as MKK4/SEK1 and MKK7, can activate JNK through phosphorylation of the conversed Thr- Pro-Tyr motif on JNK proteins. In mammalian cells, activated JNK can phosphorylate the N-terminus of c-Jun, which contains both JNK docking site and JNK phosphorylation site (ser63 and ser73), orJunD,

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -185- which lacks a JNK docking site but contains a JNK phosphorylation site. JNK is unable to phosphorylate JunB due to the lack of a JNK phosphorylation site inJunB, despite there is a functional JNK docking site. Comparison of the binding activity of JNK isoforms demonstrates that JNK2 bind c-Jun approximately 25 times more efficiently than did JNK1. Therefore, individual members of the JNK family may selectively target specific transcription factors in vivo. One of the most important functions of JNK is the regulation of apoptosis. Emerging evidence indicates that JNK activation is obligatory for apoptosis induced by both receptor-mediated ÒextrinsicÓ pathway or mitochondria-mediated ÒintrinsicÓ pathway. JNK activation may contribute to the initiation of Fas-induced apoptosis, possibly through the amplification of autocrine or paracrine Fas signaling by JNK-dependent Fas ligand (FasL) gene expression. In addition, JNK has been indicated in the apoptosis induced by Daxx, a Fas death domain (FADD) interaction protein. Through its serine/threonine kinase activity, JNK may contribute to mitochondria-mediated apoptosis by phosphorylating pro- or anti- apoptoticBcl-2 family proteins. Finally, JNK has also been indicated as an important kinase phosphorylating p53 and subsequently facilitating p53-dependent apoptotic responses. Sustained JNK activation may be responsible for the enhanced apoptosis observed in RelA-/- or Ikkb-/- mouse embryonic fibroblasts treated with TNFa. It was suggested that deficiency of RelA or IKKb caused a decreased expression of XIAP or GADD45b, which may antagonize the activation of JNK activation. However, such speculation contradicts the previous observations indicating that both GADD45b and XIAP are activators, rather than inhibitors for JNK activation. Moreover, gene profiling in our recent studies indicated no substantial difference of basal or inducible GADD45b and XIAP mRNA in wild type cells and Ikkb-/- cells. Implicated in Entity Obesity, insulin resistance, neurodegenerative diseases, inflammation, cancer. Oncogenesis Loss of expression of JNK3 has been found in some brain tumors.

External links Nomenclature Hugo MAPK10 GDB MAPK10 Entrez_Gene MAPK10 5602 mitogen-activated protein kinase 10 Cards Atlas JNK3ID427 GeneCards MAPK10 Ensembl MAPK10 Genatlas MAPK10

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -186- GeneLynx MAPK10 eGenome MAPK10 euGene 5602 Genomic and cartography MAPK10 - chr4:87294811-87731462 - 4q21.23 (hg17- GoldenPath May_2004) Ensembl MAPK10 - 4q21.23 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MAPK10 Gene and transcription

Genbank AK022161 [ SRS ] AK022161 [ ENTREZ ]

Genbank AK057723 [ SRS ] AK057723 [ ENTREZ ]

Genbank AK124791 [ SRS ] AK124791 [ ENTREZ ]

Genbank BC022492 [ SRS ] BC022492 [ ENTREZ ]

Genbank BC065516 [ SRS ] BC065516 [ ENTREZ ]

RefSeq NM_002753 [ SRS ] NM_002753 [ ENTREZ ]

RefSeq NM_138980 [ SRS ] NM_138980 [ ENTREZ ]

RefSeq NM_138981 [ SRS ] NM_138981 [ ENTREZ ]

RefSeq NM_138982 [ SRS ] NM_138982 [ ENTREZ ]

RefSeq NT_086651 [ SRS ] NT_086651 [ ENTREZ ] AceView MAPK10 AceView - NCBI TRASER MAPK10 Traser - Stanford

Unigene Hs.25209 [ SRS ] Hs.25209 [ NCBI ] HS25209 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P53779 [ SRS] P53779 [ EXPASY ] P53779 [ INTERPRO ]

Prosite PS01351 MAPK [ SRS ] PS01351 MAPK [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 Prosite PROTEIN_KINASE_ST [ Expasy ]

Interpro IPR008351 JNK_MAPK [ SRS ] IPR008351 JNK_MAPK [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR003527 MAP_kin [ SRS ] IPR003527 MAP_kin [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -187- Interpro IPR002290 Ser_thr_pkinase [ SRS ] IPR002290 Ser_thr_pkinase [ EBI ] CluSTr P53779 Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00220 S_TKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom P53779 MK10_HUMAN [ Domain structure ] P53779 MK10_HUMAN [ sequences sharing at least 1 domain ] Blocks P53779

PDB 1JNK [ SRS ] 1JNK [ PdbSum ], 1JNK [ IMB ]

PDB 1PMN [ SRS ] 1PMN [ PdbSum ], 1PMN [ IMB ]

PDB 1PMQ [ SRS ] 1PMQ [ PdbSum ], 1PMQ [ IMB ]

PDB 1PMU [ SRS ] 1PMU [ PdbSum ], 1PMU [ IMB ]

PDB 1PMV [ SRS ] 1PMV [ PdbSum ], 1PMV [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 602897 [ map ] GENECLINICS 602897

SNP MAPK10 [dbSNP-NCBI]

SNP NM_002753 [SNP-NCI]

SNP NM_138980 [SNP-NCI]

SNP NM_138981 [SNP-NCI]

SNP NM_138982 [SNP-NCI]

SNP MAPK10 [GeneSNPs - Utah] MAPK10 [SNP - CSHL] MAPK10] [HGBASE - SRS] General knowledge Family MAPK10 [UCSC Family Browser] Browser SOURCE NM_002753 SOURCE NM_138980 SOURCE NM_138981 SOURCE NM_138982 SMD Hs.25209 SAGE Hs.25209 Enzyme 2.7.1.37 [ Enzyme-SRS ] 2.7.1.37 [ Brenda-SRS ] 2.7.1.37 [ KEGG ] 2.7.1.37 [ WIT ] Amigo function|ATP binding Amigo process|JNK cascade Amigo function|JUN kinase activity Amigo function|MAP kinase activity Amigo function|MAP kinase kinase activity Amigo process|protein amino acid phosphorylation

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -188- Amigo function|protein serine/threonine kinase activity Amigo function|protein-tyrosine kinase activity Amigo process|signal transduction Amigo function|transferase activity BIOCARTA MAPKinase Signaling Pathway PubGene MAPK10 Other databases Probes Probe MAPK10 Related clones (RZPD - Berlin) PubMed PubMed 8 Pubmed reference(s) in LocusLink Bibliography Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Yang X, Khosravi-Far R, Chang HY, Baltimore D. Cell1997; 89: 1067-1076. Medline 9215629

JNK targets p53 ubiquitination and degradation in nonstressed cells. Fuchs SY, Adler V, Buschmann T, Yin Z, Wu X, Jones SN, Ronai Z. Genes Dev 1998; 12: 2658-2663. Medline 9732264

A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Takekawa M, Saito H. Cell 1998; 95: 521-530. Medline 9827804

Signal transduction by the JNK group of MAP kinases. Davis RJ Cell 2000; 103: 239-252.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -189- Medline 11057897

Inhibition of JNK activation through NF-kappaB target genes. Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M, Lin A. Nature 2001; 414: 313-317. Medline 11713531

The c-Jun NH2-terminal kinase3 (JNK3) gene: genomic structure, chromosomal assignment, and loss of expression in brain tumors. Yoshida S, Fukino K, Harada H, Nagai H, Imoto I, Inazawa J, Takahashi H, Teramoto A, Emi M. J Hum Genet 2001; 46: 182-187. Medline 11322657

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Fei Chen 2003 Citation This paper should be referenced as such : Chen F . MAPK10 (mitogen-activated protein kinase 10). Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/JNK3ID427.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -190- Atlas of Genetics and Cytogenetics in Oncology and Haematology

JUNB

Identity Other JUN-B names JUN protooncogene homolog B Hugo JUNB Location 19p13.2 DNA/RNA Description The JUNB gene maps on chromosome 19p13.2 covering 1820 bp. Transcription It contains no confirmed intron. Therefore, no alternative splicing transcripts have been identified. Protein

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -191- Description JUNB has 347 amino acids with a predicted molecular weight 35,9 kD. Structurally, JUNB is similar to JUN, which contains a JNK docking site, nuclear localization signal, basic domain for DNA binding and a leucine zipper domain for dimerization. However, JUNB does not contain a JUNK phosphorylation site. Thus, the transactivation activity of JUNB is not regulated by JNK. Expression Ubiquitously expressed. Localisation Nuclear Function JUNB is a member of JUN family (JUN, JUNB and JUND) that can dimerize with one another, or with members of Fos and ATF families, to form AP-1 transcription factor. Comparing with JUN, the transactivation activity of JUNB is much weaker. Due to the small differences on the amino acid sequences in the basic DNA bindind domain, and leucine zipper domain, JUNB requires multiple AP-1 DNA binding sites for sufficient DNA binding. A number of studies demonstrated that JUNB antagonizes the functions of JUN in cell cycle regulation, proliferation and transformation by competing with JUN to form less efficient transactivating dimers. Thus, JUNB was considered as a tumor suppressor. In gene knockout studies, mice lacking Jun gene die during embryonic day 12.5 and 13.5, whereas embryos lacking JunB die earlier, around day 9.5, owing to vascular defects in the placenta and extraembryonic tissue. Interestingly; gene knock-in experiment indicated that JUNB could partially substitute the activities of JUN in mouse development and cell proliferation. As possible explanation for this is that in presence of JUN, JUNB is a negative regulator for JUN. In contrast, in the absence of JUN, JUNB may substitute JUN and activate AP-1 target genes required for development and cell proliferation. Implicated in Entity Inflammation, cancer Oncogenesis Decreased expression of JUNB has been observed in certain human cancer. However, no mutation, rearrangement or amplification of JunB gene has been reported.

External links Nomenclature Hugo JUNB GDB JUNB Entrez_Gene JUNB 3726 jun B proto-oncogene Cards Atlas JUNBID178 GeneCards JUNB Ensembl JUNB CancerGene JUNB

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -192- Genatlas JUNB GeneLynx JUNB eGenome JUNB euGene 3726 Genomic and cartography JUNB - 19p13.2 chr19:12763310-12765124 + 19p13.13 (hg17- GoldenPath May_2004) Ensembl JUNB - 19p13.13 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene JUNB Gene and transcription

Genbank AY751746 [ SRS ] AY751746 [ ENTREZ ]

Genbank M29039 [ SRS ] M29039 [ ENTREZ ]

Genbank U20734 [ SRS ] U20734 [ ENTREZ ]

Genbank BC004250 [ SRS ] BC004250 [ ENTREZ ]

Genbank BC009465 [ SRS ] BC009465 [ ENTREZ ]

RefSeq NM_002229 [ SRS ] NM_002229 [ ENTREZ ]

RefSeq NT_086897 [ SRS ] NT_086897 [ ENTREZ ] AceView JUNB AceView - NCBI TRASER JUNB Traser - Stanford

Unigene Hs.25292 [ SRS ] Hs.25292 [ NCBI ] HS25292 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P17275 [ SRS] P17275 [ EXPASY ] P17275 [ INTERPRO ]

Prosite PS50217 BZIP [ SRS ] PS50217 BZIP [ Expasy ]

Prosite PS00036 BZIP_BASIC [ SRS ] PS00036 BZIP_BASIC [ Expasy ] Interpro IPR008917 Euk_transcr_DNA [ SRS ] IPR008917 Euk_transcr_DNA [ EBI ]

Interpro IPR005643 JNK [ SRS ] IPR005643 JNK [ EBI ]

Interpro IPR002112 Leuzip_Jun [ SRS ] IPR002112 Leuzip_Jun [ EBI ]

Interpro IPR004827 TF_bZIP [ SRS ] IPR004827 TF_bZIP [ EBI ] CluSTr P17275

Pfam PF00170 bZIP [ SRS ] PF00170 bZIP [ Sanger ] pfam00170 [ NCBI-CDD ]

Pfam PF03957 Jun [ SRS ] PF03957 Jun [ Sanger ] pfam03957 [ NCBI-CDD ] Blocks P17275 Polymorphism : SNP, mutations, diseases OMIM 165161 [ map ] GENECLINICS 165161

SNP JUNB [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -193- SNP NM_002229 [SNP-NCI]

SNP JUNB [GeneSNPs - Utah] JUNB [SNP - CSHL] JUNB] [HGBASE - SRS] General knowledge Family JUNB [UCSC Family Browser] Browser SOURCE NM_002229 SMD Hs.25292 SAGE Hs.25292 Amigo function|RNA polymerase II transcription factor activity Amigo component|chromatin Amigo component|nucleus Amigo process|regulation of transcription from Pol II promoter Amigo function|transcription coactivator activity Amigo function|transcription corepressor activity Amigo function|transcription factor activity BIOCARTA GATA3 participate in activating the Th2 cytokine genes expression PubGene JUNB Other databases Probes Probe JUNB Related clones (RZPD - Berlin) PubMed PubMed 15 Pubmed reference(s) in LocusLink Bibliography JunB is essential for mammalian placentation. Schorpp-Kistner M, Wang ZQ, Angel P, Wagner EF. Embo J 1999; 18 : 934-948. Medline 10022836

JunB can substitute for Jun in mouse development and cell proliferation. Passegue E, Jochum W, Behrens A, Ricci R, Wagner EF. Nat Genet 2002; 30 : 158-166. Medline 11818961

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Fei Chen 2003

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -194- Citation This paper should be referenced as such : Chen F . JUNB. Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/JUNBID178.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -195- Atlas of Genetics and Cytogenetics in Oncology and Haematology

JUN-D proto-oncogene

Identity Hugo JUND Location 19p13.1-p12 DNA/RNA Description The gene for JUND is located on the region of chromosome 19p13.1- p12 covering 1409bp. Similar to other members of JUN family, the JunD gene is also intronless. Protein

Description The JUND protein contains 347 amino acids with a predicted molecular weight 35.2 kD. From N-terminus to C-terminus, JUND has a JNK phosphorylating motif (Ser90/Ser100), DNA binding domain, nuclear localization signal (NLS), and a leucine zipper domain. Since this protein lacks the JNK docking site, JUND can only be weakly phosphorylated by JNK. Although the JunD gene has no introns and produces a single transcript, the JUND mRNA translates two JUND protein isoforms, JUND-L and JUND-S. By using a different in-frame translational initiation site, the third AUG codon in JUND mRNA, the short version of JUND, JUND-S, was generated that lacks the N- terminal 43 amino acids. Due to this N-terminal truncation, the JUND-S is unable to associate with Menin, another tumor suppressor protein. Expression JUND is the most broadly expressed member of the JUN family but

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -196- expressed at low level. Localisation The subcellular location of this protein is most likely in the nucleus. Less likely possibilities are in the cytoplasm and in the mitochondria. Function JUND is a member of the JUN family of basic region leucine zipper (bZIP) DNA-binding proteins. Analysis of the protein expression levels demonstrated an opposite expression pattern between JUN and JUND. When cells entry into the G0 phase of the cell cycle by serum starvation, JUN level decreases and JUND level increases. Similar to JUNB, JUND has been shown as an antagonist of JUN in the induction of cyclin D1. Therefore, increasing the abundance of JUND may maintain the cells in a quiescent state. Transformation studies demonstrated that excess JUND protein could partially suppress the transformed phenotype mediated by JUN in cooperation with Ras. The effect of JUND in development appears to be marginal. Mice lacking JUND are viable with only mild defects in growth and spermatogenesis, whereas mice lacking JUN or JUNB die in embryo. External links Nomenclature Hugo JUND GDB JUND Entrez_Gene JUND 3727 jun D proto-oncogene Cards Atlas JUNDID179 GeneCards JUND Ensembl JUND CancerGene JUND Genatlas JUND GeneLynx JUND eGenome JUND euGene 3727 Genomic and cartography JUND - chr19:18251570-18253468 - 19p13.11 (hg17- GoldenPath May_2004) Ensembl JUND - 19p13.11 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene JUND Gene and transcription

Genbank X51346 [ SRS ] X51346 [ ENTREZ ]

Genbank X56681 [ SRS ] X56681 [ ENTREZ ]

RefSeq NM_005354 [ SRS ] NM_005354 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -197- RefSeq NT_086897 [ SRS ] NT_086897 [ ENTREZ ] AceView JUND AceView - NCBI TRASER JUND Traser - Stanford

Unigene Hs.2780 [ SRS ] Hs.2780 [ NCBI ] HS2780 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P17535 [ SRS] P17535 [ EXPASY ] P17535 [ INTERPRO ]

Prosite PS50217 BZIP [ SRS ] PS50217 BZIP [ Expasy ]

Prosite PS00036 BZIP_BASIC [ SRS ] PS00036 BZIP_BASIC [ Expasy ] Interpro IPR008917 Euk_transcr_DNA [ SRS ] IPR008917 Euk_transcr_DNA [ EBI ]

Interpro IPR005643 JNK [ SRS ] IPR005643 JNK [ EBI ]

Interpro IPR002112 Leuzip_Jun [ SRS ] IPR002112 Leuzip_Jun [ EBI ]

Interpro IPR004827 TF_bZIP [ SRS ] IPR004827 TF_bZIP [ EBI ] CluSTr P17535

Pfam PF00170 bZIP [ SRS ] PF00170 bZIP [ Sanger ] pfam00170 [ NCBI-CDD ]

Pfam PF03957 Jun [ SRS ] PF03957 Jun [ Sanger ] pfam03957 [ NCBI-CDD ]

Smart SM00338 BRLZ [EMBL] Blocks P17535 Polymorphism : SNP, mutations, diseases OMIM 165162 [ map ] GENECLINICS 165162

SNP JUND [dbSNP-NCBI]

SNP NM_005354 [SNP-NCI]

SNP JUND [GeneSNPs - Utah] JUND [SNP - CSHL] JUND] [HGBASE - SRS] General knowledge Family JUND [UCSC Family Browser] Browser SOURCE NM_005354 SMD Hs.2780 SAGE Hs.2780 Amigo function|RNA polymerase II transcription factor activity Amigo component|chromatin Amigo component|nucleus Amigo process|regulation of transcription from Pol II promoter Amigo function|transcription factor activity BIOCARTA B Cell Survival Pathway BIOCARTA FOSB gene expression and drug abuse PubGene JUND Other databases

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -198- Probes Probe JUND Related clones (RZPD - Berlin) PubMed PubMed 13 Pubmed reference(s) in LocusLink Bibliography C-jun is essential for normal mouse development and hepatogenesis. Hilberg F, Aguzzi A, Howells N, Wagner EF. Nature 1993; 365: 179-181. Medline 8371760

Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Pfarr CM, Mechta F, Spyrou G, Lallemand D, Carillo S, Yaniv M. Cell 1994; 76: 747-760. Medline 8124713

Variations in Jun and Fos protein expression and AP-1 activity in cycling, resting and stimulated fibroblasts. Lallemand D, Spyrou G, Yaniv M, Pfarr CM. Oncogene 1997; 14: 819-830. Medline 9047389

Two proteins translated by alternative usage of initiation codons in mRNA encoding a JunD transcriptional regulator. Okazaki S, Ito T, Ui M, Watanabe T, Yoshimatsu K, Iba H. Biochem Biophys Res Commun 1998; 250: 347-353. Medline 9753632

JunB is essential for mammalian placentation. Schorpp-Kistner M, Wang ZQ, Angel P, Wagner EF. Embo J 1999; 18: 934-948. Medline 10022836

Targeted disruption of the murine junD gene results in multiple defects in male reproductive function. Thepot D, Weitzman JB, Barra J, Segretain D, Stinnakre MG, Babinet C, Yaniv M. Development 2000; 127: 143-153. Medline 10654608

The mammalian Jun proteins: redundancy and specificity. Mechta-Grigoriou F, Gerald D, Yaniv M. Oncogene 2001; 20: 2378-2389. Medline 11402334

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -199- Differential binding of the Menin tumor suppressor protein to JunD isoforms. Yazgan O, Pfarr CM. Cancer Res 2001; 61: 916-920. Medline 11221882

Translational regulation of the JunD messenger RNA. Short JD, Pfarr CM. J Biol Chem 2002; 277: 32697-32705. Medline 12105216

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Fei Chen 2003 Citation This paper should be referenced as such : Chen F . JUN-D proto-oncogene. Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/JUNDID179.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -200- Atlas of Genetics and Cytogenetics in Oncology and Haematology

JUN (V-Jun sarcoma virus 17 oncogene homolog (avian))

Identity Other c-jun names Activator Protein-1 Hugo JUN Location 1p32-p31 DNA/RNA Description The Jun gene maps on chromosome 1p32-p31 spanning 333799bp. The study by Hattori et al suggested that the Jun gene has no introns. Transcription Due to 5' and 3' heterogeneities, several transcripts of Jun mRNA has been identified. The predicted molecular weight of JUN protein is 41.9 kD. Protein

Description The JUN protein was originally identified as an oncoprotein encoded by a cellular insert in the genome of avian sarcoma virus 17. Following studies demonstrated that JUN is a critical component of AP-1 transcription factor that recognizes the palindromic DNA sequence TGAC/GTCA, the so-called TPA response element (TRE), in the promoter or intron region of a number of genes. JUN can stably associate with itself or Fos protein to form AP-1 complex. JUN can also interact with some activating transcription factor (ATF) members, such as ATF2, ATF3 and ATF4, to form heterodimers that bind to the cAMP- responsive element (CRE) DNA sequence, TGACGTCA. All JUN proteins from different species contain a N-terminal JNK docking domain (delta domain) adjacent to the JNK phosphorylating site Ser63/73. In the C-terminal, there is a basic domain for DNA binding, followed by a nuclear localization signal (NLS) and a leucine zipper motif for dimerization with partner proteins.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -201- Expression Ubiquitously expressed. Localisation Nuclear and mitochondria. Function JUN is the most important component of AP-1 transcription factors, and its transcriptional activity is possibly attenuated by JUNB or JUND. It has been well accepted that JUN regulates cell proliferation, apoptosis and transformation. JUN promotes cell cycle transition from G1 phase to S phase by up-regulating cyclin D1 expression and antagonizing the function of p53and p21. The JUN protein is involved in both the induction and prevention of apoptosis, possibly dependent on the types and development stages of cells. JUN-dependent induction of pro- apoptotic protein FasL and Bim has been demonstrated in several experimental systems. However, evidence indicating an anti-apoptotic activity of JUN has also been provided by the fact that deficiency of Jun gene causes massive hepatocyte apoptosis. The potential oncogenic transformation of JUN has been revealed by overexpression experiments. This effect of JUN may partially through the induction of certain JUN targeting genes, such as heparin-bind epidermal growth factor-like growth factor (HB-EGF), proliferin and Jun-activated gene in chicken embryo fibroblasts (JAC). Implicated in Entity Inflammation

Entity cancer Oncogenesis Overexpression of JUN has been observed in certain human cancer. However, no mutation, rearrangement or amplification of Jun gene has been reported.

External links Nomenclature Hugo JUN GDB JUN Entrez_Gene JUN 3725 v-jun sarcoma virus 17 oncogene homolog (avian) Cards Atlas JUNID151 GeneCards JUN Ensembl JUN CancerGene JUN Genatlas JUN GeneLynx JUN eGenome JUN euGene 3725 Genomic and cartography

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -202- GoldenPath JUN - chr1:58958484-58961806 - 1p32.1 (hg17-May_2004) Ensembl JUN - 1p32.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene JUN Gene and transcription

Genbank AY217548 [ SRS ] AY217548 [ ENTREZ ]

Genbank J04111 [ SRS ] J04111 [ ENTREZ ]

Genbank BC002646 [ SRS ] BC002646 [ ENTREZ ]

Genbank BC006175 [ SRS ] BC006175 [ ENTREZ ]

Genbank BC009874 [ SRS ] BC009874 [ ENTREZ ]

RefSeq NM_002228 [ SRS ] NM_002228 [ ENTREZ ]

RefSeq NT_086582 [ SRS ] NT_086582 [ ENTREZ ] AceView JUN AceView - NCBI TRASER JUN Traser - Stanford

Unigene Hs.525704 [ SRS ] Hs.525704 [ NCBI ] HS525704 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P05412 [ SRS] P05412 [ EXPASY ] P05412 [ INTERPRO ]

Prosite PS50217 BZIP [ SRS ] PS50217 BZIP [ Expasy ]

Prosite PS00036 BZIP_BASIC [ SRS ] PS00036 BZIP_BASIC [ Expasy ] Interpro IPR008917 Euk_transcr_DNA [ SRS ] IPR008917 Euk_transcr_DNA [ EBI ]

Interpro IPR005643 JNK [ SRS ] IPR005643 JNK [ EBI ]

Interpro IPR002112 Leuzip_Jun [ SRS ] IPR002112 Leuzip_Jun [ EBI ]

Interpro IPR004827 TF_bZIP [ SRS ] IPR004827 TF_bZIP [ EBI ] CluSTr P05412

Pfam PF00170 bZIP [ SRS ] PF00170 bZIP [ Sanger ] pfam00170 [ NCBI-CDD ]

Pfam PF03957 Jun [ SRS ] PF03957 Jun [ Sanger ] pfam03957 [ NCBI-CDD ]

Smart SM00338 BRLZ [EMBL] Blocks P05412

PDB 1A02 [ SRS ] 1A02 [ PdbSum ], 1A02 [ IMB ]

PDB 1FOS [ SRS ] 1FOS [ PdbSum ], 1FOS [ IMB ]

PDB 1JNM [ SRS ] 1JNM [ PdbSum ], 1JNM [ IMB ]

PDB 1JUN [ SRS ] 1JUN [ PdbSum ], 1JUN [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 165160 [ map ] GENECLINICS 165160

SNP JUN [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -203- SNP NM_002228 [SNP-NCI]

SNP JUN [GeneSNPs - Utah] JUN [SNP - CSHL] JUN] [HGBASE - SRS] General knowledge Family JUN [UCSC Family Browser] Browser SOURCE NM_002228 SMD Hs.525704 SAGE Hs.525704 Amigo function|RNA polymerase II transcription factor activity Amigo component|nuclear chromosome Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity BIOCARTA The 4-1BB-dependent immune response Angiotensin II mediated activation of JNK Pathway via Pyk2 BIOCARTA dependent signaling BIOCARTA Pertussis toxin-insensitive CCR5 Signaling in Macrophage BIOCARTA IL12 and Stat4 Dependent Signaling Pathway in Th1 Development BIOCARTA TPO Signaling Pathway BIOCARTA Agrin in Postsynaptic Differentiation BIOCARTA Oxidative Stress Induced Gene Expression Via Nrf2 BIOCARTA ATM Signaling Pathway BIOCARTA BCR Signaling Pathway Role of EGF Receptor Transactivation by GPCRs in Cardiac BIOCARTA Hypertrophy BIOCARTA Cadmium induces DNA synthesis and proliferation in macrophages BIOCARTA D4-GDI Signaling Pathway Repression of Pain Sensation by the Transcriptional Regulator BIOCARTA DREAM BIOCARTA EGF Signaling Pathway BIOCARTA EPO Signaling Pathway BIOCARTA METS affect on Macrophage Differentiation BIOCARTA FAS signaling pathway ( CD95 ) BIOCARTA Fc Epsilon Receptor I Signaling in Mast Cells BIOCARTA Inhibition of Cellular Proliferation by Gleevec BIOCARTA Signaling Pathway from G-Protein Families BIOCARTA Hypoxia-Inducible Factor in the Cardiovascular System BIOCARTA IGF-1 Signaling Pathway BIOCARTA Signal transduction through IL1R BIOCARTA IL 2 signaling pathway

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -204- BIOCARTA IL 6 signaling pathway BIOCARTA Insulin Signaling Pathway BIOCARTA Integrin Signaling Pathway BIOCARTA Keratinocyte Differentiation BIOCARTA Signaling of Hepatocyte Growth Factor Receptor BIOCARTA Nerve growth factor pathway (NGF) BIOCARTA The information-processing pathway at the IFN-beta enhancer BIOCARTA PDGF Signaling Pathway Mechanism of Gene Regulation by Peroxisome Proliferators via BIOCARTA PPARa(alpha) BIOCARTA Links between Pyk2 and Map Kinases BIOCARTA TNF/Stress Related Signaling BIOCARTA T Cell Receptor Signaling Pathway BIOCARTA TNFR1 Signaling Pathway BIOCARTA Toll-Like Receptor Pathway BIOCARTA TSP-1 Induced Apoptosis in Microvascular Endothelial Cell PubGene JUN Other databases Probes Probe JUN Related clones (RZPD - Berlin) PubMed PubMed 74 Pubmed reference(s) in LocusLink Bibliography Structure and chromosomal localization of the functional intronless human JUN protooncogene. Hattori K, Angel P, Le Beau MM., Karin M. Proc Natl Acad Sci USA 1988; 85: 9148-9152. Medline 3194415

AP-1 as a regulator of cell life and death Shaulian E, Karin M. Nat Cell Biol 2002; 4: E131-136. Rewiew. Medline 11988758

Jun, the oncoprotein. Vogt, PK Oncogene 2001; 20: 2365-2377. Medline 11402333

Fortuitous convergences: the beginnings of JUN. Vogt, PK.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -205- Nat Rev Cancer 2002; 2: 465-469. Review Medline 12189388

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Fei Chen 2003 Citation This paper should be referenced as such : Chen F . JUN (V-Jun sarcoma virus 17 oncogene homolog (avian)). Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/JUNID151.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -206- Atlas of Genetics and Cytogenetics in Oncology and Haematology

RECQL

Identity Hugo RECQL Location 12p12-p11 DNA/RNA Transcription Two alternatively spliced transcripts, which encode the same isoform but differ in their 5' and 3' UTRs, have been described. Coding region: 1977 bp. Three RNA bands of 4.0, 3.3 and 2.2 kb were detected in HeLa cells by Northern blotting. Protein

Description 659 amino acids; contains one ATP binding site and one DexH box. Two other putative isoforms resulting from an alternative mRNA splicing may exist. Localisation Nuclear Function 3'-5' DNA helicase. Replication Protein A stimulates its helicase activity. Homology Homologous to RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. In particular, similarities with the four known human members in the RecQ subfamily, human RecQL4, human RecQL5, human BLM, the product of the Bloom syndrome gene and human WRN, the product of the Werner syndrome gene. Mutations Note Not described, and correlation with genetic disorder, if any, is (yet) unknown. External links Nomenclature Hugo RECQL GDB RECQL Entrez_Gene RECQL 5965 RecQ protein-like (DNA helicase Q1-like) Cards Atlas RECQLID283 GeneCards RECQL Ensembl RECQL Genatlas RECQL

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -207- GeneLynx RECQL eGenome RECQL euGene 5965 Genomic and cartography RECQL - chr12:21513965-21545796 - 12p12.1 (hg17- GoldenPath May_2004) Ensembl RECQL - 12p12.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RECQL Gene and transcription

Genbank AY157499 [ SRS ] AY157499 [ ENTREZ ]

Genbank BC001052 [ SRS ] BC001052 [ ENTREZ ]

Genbank BT007119 [ SRS ] BT007119 [ ENTREZ ]

Genbank D37984 [ SRS ] D37984 [ ENTREZ ]

Genbank L36140 [ SRS ] L36140 [ ENTREZ ]

RefSeq NM_002907 [ SRS ] NM_002907 [ ENTREZ ]

RefSeq NM_032941 [ SRS ] NM_032941 [ ENTREZ ]

RefSeq NT_086793 [ SRS ] NT_086793 [ ENTREZ ] AceView RECQL AceView - NCBI TRASER RECQL Traser - Stanford

Unigene Hs.235069 [ SRS ] Hs.235069 [ NCBI ] HS235069 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P46063 [ SRS] P46063 [ EXPASY ] P46063 [ INTERPRO ]

Interpro IPR001410 DEAD [ SRS ] IPR001410 DEAD [ EBI ]

Interpro IPR001650 Helicase_C [ SRS ] IPR001650 Helicase_C [ EBI ]

Interpro IPR004589 RecQ [ SRS ] IPR004589 RecQ [ EBI ] CluSTr P46063 Pfam PF00270 DEAD [ SRS ] PF00270 DEAD [ Sanger ] pfam00270 [ NCBI-CDD ]

PF00271 Helicase_C [ SRS ] PF00271 Helicase_C [ Sanger Pfam ] pfam00271 [ NCBI-CDD ]

Smart SM00487 DEXDc [EMBL]

Smart SM00490 HELICc [EMBL] Blocks P46063 Polymorphism : SNP, mutations, diseases OMIM 600537 [ map ] GENECLINICS 600537

SNP RECQL [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -208- SNP NM_002907 [SNP-NCI]

SNP NM_032941 [SNP-NCI]

SNP RECQL [GeneSNPs - Utah] RECQL [SNP - CSHL] RECQL] [HGBASE - SRS] General knowledge Family RECQL [UCSC Family Browser] Browser SOURCE NM_002907 SOURCE NM_032941 SMD Hs.235069 SAGE Hs.235069 Amigo function|ATP binding Amigo function|ATP-dependent DNA helicase activity Amigo function|DNA binding Amigo process|DNA repair Amigo function|hydrolase activity Amigo component|nucleus PubGene RECQL Other databases Probes Probe RECQL Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography Cloning and characterization of RECQL, a potential human homologue of the Escherichia coli DNA helicase RecQ. Puranam KL, Blackshear PJ. J Biol Chem. 1994; 269: 29838-29845. Medline 7961977

Molecular cloning of cDNA encoding human DNA helicase Q1 which has homology to Escherichia coli Rec Q helicase and localization of the gene at chromosome 12p12. Seki M, Miyazawa H, Tada S, Yanagisawa J, Yamaoka T, Hoshino S, Ozawa K, Eki T, Nogami M, Okumura K, et al. Nucleic Acids Res. 1994; 22: 4566-4573. Medline 7527136

Chromosomal localization of the gene encoding the human DNA helicase RECQL and its mouse homologue. Puranam KL, Kennington E, Sait SN, Shows TB, Rochelle JM, Seldin MF, Blackshear PJ.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -209- Genomics. 1995; 26: 595-598. Medline 7607686

Molecular cloning of a splicing variant of human RECQL helicase. Zhang AH ; Xi X. Biochem Biophys Res Commun. 2002, 298:789-92. Medline 12419324

Characterization of the DNA unwinding activity of human RECQ1. A helicase specifically stimulated by hRPA. Cui S, Klima R, Ochem A, Arosio D, Falaschi A, Vindigni A. J Biol Chem. 2003; 278(3): 1424-1432 Medline 12419808

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Mounira Amor-Guéret 2003 Citation This paper should be referenced as such : Amor-Guéret M . RECQL. Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/RECQLID283.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -210- Atlas of Genetics and Cytogenetics in Oncology and Haematology

BCL9 (B-cell CLL/lymphoma 9)

Identity Hugo BCL9 Location 1q21 DNA/RNA Description 10 exons spanning 85 kb. Transcription transcripts of 1.6, 4.2, and 6.3 kb. Protein

Description 1426 amino acids, 149 kDa. Expression wide Function Binds to beta-catenin required for Wnt signal transduction Homology drosophila segment polarity gene legless, encoding wingless-armadillo (WNT - beta-catenin) signaling molecule Implicated in Entity t(1;14)(q21;q32) and t(1;22)(q21;q11) Disease acute lymphoblastic leukemia and non Hodgkin lymphoma Hybrid/Mutated BCL9 is juxtaposed either with the immunoglobulin heavy chain locus Gene IgH (14q32) or the lambda light-chain locus Igl (22q11)

External links Nomenclature Hugo BCL9 GDB BCL9 Entrez_Gene BCL9 607 B-cell CLL/lymphoma 9 Cards Atlas BCL9ID466 GeneCards BCL9 Ensembl BCL9 CancerGene BCL9 Genatlas BCL9 GeneLynx BCL9

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -211- eGenome BCL9 euGene 607 Genomic and cartography BCL9 - 1q21 chr1:144237998-144322828 + 1q21.1 (hg17- GoldenPath May_2004) Ensembl BCL9 - 1q21.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BCL9 Gene and transcription

Genbank AL359207 [ SRS ] AL359207 [ ENTREZ ]

Genbank Y13620 [ SRS ] Y13620 [ ENTREZ ]

RefSeq NM_004326 [ SRS ] NM_004326 [ ENTREZ ]

RefSeq NT_086594 [ SRS ] NT_086594 [ ENTREZ ] AceView BCL9 AceView - NCBI TRASER BCL9 Traser - Stanford

Unigene Hs.415209 [ SRS ] Hs.415209 [ NCBI ] HS415209 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O00512 [ SRS] O00512 [ EXPASY ] O00512 [ INTERPRO ] CluSTr O00512 Blocks O00512 Polymorphism : SNP, mutations, diseases OMIM 602597 [ map ] GENECLINICS 602597

SNP BCL9 [dbSNP-NCBI]

SNP NM_004326 [SNP-NCI]

SNP BCL9 [GeneSNPs - Utah] BCL9 [SNP - CSHL] BCL9] [HGBASE - SRS] General knowledge Family BCL9 [UCSC Family Browser] Browser SOURCE NM_004326 SMD Hs.415209 SAGE Hs.415209 Amigo process|Wnt receptor signaling pathway Amigo component|nucleus PubGene BCL9 Other databases Probes

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -212- Probe BCL9 Related clones (RZPD - Berlin) PubMed PubMed 2 Pubmed reference(s) in LocusLink Bibliography Molecular cloning of translocation t(1;14)(q21;q32) defines a novel gene (BCL9) at chromosome 1q21. Willis TG, Zalcberg IR, Coignet LJ, Wlodarska I, Stul M, Jadayel DM, Bastard C, Treleaven JG, Catovsky D, Silva ML, Dyer MJ. Blood 1998; 91: 1873-1881. Medline 9490669

Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, Murone M, Zullig S, Basler K. Cell. 2002; 109: 47-60. Medline 11955446

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Jean-Loup Huret, Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL, Senon S . BCL9 (B-cell CLL/lymphoma 9). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/BCL9ID466.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -213- Atlas of Genetics and Cytogenetics in Oncology and Haematology

WFDC1 (WAP four-disulfide core domain 1) (updated: old version not available)

Identity Other ps20 names Hugo WFDC1 Location 16q24.1 DNA/RNA Description The gene encompasses 35 kb of DNA; 7 exons. Transcription 1366 nucleotides mRNA; 660 bp open reading frame. Protein

Representation of the position of the conserved cysteines for the category of "four-disulfide core" domain and the location of the signature pattern for such a domain in the human WFDC1 amino acid sequence.

Description 220 amino acids; 24 kDa protein. Like rat ps20, human ps20 protein contains a WAP signature domain. Expression Widely expressed, absent in thymus. Function The rat homologue of ps20 was originally identified as a secreted growth inhibitor. These growth regulatory effects and the cell phenotypic properties in vitro, suggest that ps20 may function as a mediator of stromal-epithelial interactions and contribute to the maintenance of tissue homeostasis. The ps20 protein is assumed to function as a protease inhibitor. In vitro studies indicate that exogeneous addition of ps20 protein stimulates endothelial cell migration, and promotes angiogenesis and tumour growth in a xenograft model of prostate

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -214- cancer. Homology The human WFDC1 protein shares approximately 86% and 88% identity with the rat and mouse proteins, respectively. WFDC1 is related to a family of human proteins that also have homology with WAP. The WFDC1 gene organization presents similarities with that of the KAL gene, which extends on 210 kb of DNA, includes 14 exons and is the largest gene in the WAP signature domain family. Mutations Note Although WFDC1 was mapped to human chromosome 16q24, an area of frequent loss of heterozygosity (LOH) in prostate and hepatocellular carcinomas, no tumour-associated mutations were identified in the coding region of WFDC1 in these cancer types. Mutations in WFDC1 gene resulting in Gly9Asp, Pro211Ser and Lys217Arg substitutions have been found at low frequency in the stroma of breast carcinomas. One mutation resulting in a Pro167Ser substitution has been identified in the epithelium of breast carcinoma. Implicated in Disease Prostate cancer Oncogenesis WFDC1 is significantly down-regulated in prostate cancer making it a candidate tumour suppressor gene. However, WFDC1 seems predominantly expressed in the stroma of normal prostate. In tumors, decreased stromal WFDC1 expression has been associated with increased epithelial WFDC1 expression. This correlate with shorter recurrence-free survival times and may indicate progression to a more aggressive epithelial phenotype and an epithelial mesenchymal transition process.

External links Nomenclature Hugo WFDC1 GDB WFDC1 Entrez_Gene WFDC1 58189 WAP four-disulfide core domain 1 Cards Atlas WFDC1ID424 GeneCards WFDC1 Ensembl WFDC1 CancerGene WFDC1 Genatlas WFDC1 GeneLynx WFDC1 eGenome WFDC1 euGene 58189 Genomic and cartography

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -215- WFDC1 - 16q24.1 chr16:82885902-82920950 + 16q24.1 (hg17- GoldenPath May_2004) Ensembl WFDC1 - 16q24.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene WFDC1 Gene and transcription

Genbank AF169631 [ SRS ] AF169631 [ ENTREZ ]

Genbank AF302109 [ SRS ] AF302109 [ ENTREZ ]

Genbank AK075061 [ SRS ] AK075061 [ ENTREZ ]

Genbank AL713785 [ SRS ] AL713785 [ ENTREZ ]

Genbank BC029159 [ SRS ] BC029159 [ ENTREZ ]

RefSeq NM_021197 [ SRS ] NM_021197 [ ENTREZ ]

RefSeq NT_086855 [ SRS ] NT_086855 [ ENTREZ ] AceView WFDC1 AceView - NCBI TRASER WFDC1 Traser - Stanford

Unigene Hs.36688 [ SRS ] Hs.36688 [ NCBI ] HS36688 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9HC57 [ SRS] Q9HC57 [ EXPASY ] Q9HC57 [ INTERPRO ]

PS00317 4_DISULFIDE_CORE [ SRS ] PS00317 Prosite 4_DISULFIDE_CORE [ Expasy ]

Interpro IPR008197 WAP [ SRS ] IPR008197 WAP [ EBI ] CluSTr Q9HC57

Pfam PF00095 WAP [ SRS ] PF00095 WAP [ Sanger ] pfam00095 [ NCBI-CDD ]

Smart SM00217 WAP [EMBL] Blocks Q9HC57 Polymorphism : SNP, mutations, diseases OMIM 605322 [ map ] GENECLINICS 605322

SNP WFDC1 [dbSNP-NCBI]

SNP NM_021197 [SNP-NCI]

SNP WFDC1 [GeneSNPs - Utah] WFDC1 [SNP - CSHL] WFDC1] [HGBASE - SRS] General knowledge Family WFDC1 [UCSC Family Browser] Browser SOURCE NM_021197 SMD Hs.36688 SAGE Hs.36688 Amigo component|extracellular space

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -216- Amigo process|negative regulation of cell growth Amigo function|serine-type endopeptidase inhibitor activity PubGene WFDC1 Other databases Probes Probe WFDC1 Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Responses of NBT-II bladder carcinoma cells to conditioned medium from normal fetal urogenital sinus. Rowley DR, Tindall DJ. Cancer Res 1987; 47: 2955-2960. Medline 3567912

Characterization of a fetal urogenital sinus mesenchymal cell line U4F: secretion of a negative growth factor regulatory activity. Rowley DR. In Vitro Cell Dev Biol 1992; 28A: 29-38. Medline 1730568

Purification of a novel protein (ps20) from urogenital sinus mesenchymal cells with growth inhibitory properties in vitro. Rowley DR, Dang TD, Larsen M, Gerdes MJ, McBride L, Lu B. J Biol Chem 1995; 270: 22058-22065. Medline 7665628

Molecular cloning and expression of ps20 growth inhibitor: a novel WAP-type 'four-disulfide core' domain protein expressed in smooth muscle. Larsen M, Ressler SJ, Lu B, Gerdes MJ, McBride L, Dang TD, Rowley DR. J Biol Chem 1998; 273: 4574-4584. Medline 9468514

The WFDC1 gene encoding ps20 localizes to 16q24, a region of LOH in multiple cancers. Larsen M, Ressler SJ, Gerdes MJ, Lu B, Byron M, Lawrence JB, Rowley DR. Mamm Genome 2000; 11: 767-773. Medline 10967136

Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C. Nat Genet 2002; 32: 355-357. Medline 12379854

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -217-

Analysis of alterations of WFDC1, a new putative tumour suppressor gene, in hepatocellular carcinoma. Saffroy R, Riou P, Soler G, Azoulay D, Emile JF, Debuire B, Lemoine A. Eur J Hum Genet 2002; 10: 239-244. Medline 12032731

Promotion of angiogenesis by ps20 in the differential reactive stroma prostate cancer xenograft model. McAlhany SJ, Ressler SJ, Larsen M, Tuxhorn JA, Yang F, Dang TD, Rowley DR. Cancer Res 2003; 63: 5859-5865. Medline 145228910

Integration of high-resolution array comparative genomic hybridization analysis of chromosome 16q with expression array data refines common regions of loss at 16q23-qter and identifies underlying candidate tumor suppressor genes in prostate cancer. Watson JE, Doggett NA, Albertson DG, Andaya A, Chinnaiyan A, van Dekken H, Ginzinger D, Haqq C, James K, Kamkar S, Kowbel D, Pinkel D, Schmitt L, Simko JP, Volik S, Weinberg VK, Paris PL, Collins C. Oncogene 2004; 23: 3487-3494. Medline 15007382

Decreased stromal expression and increased epithelial expression of WFDC1/ps20 in prostate cancer is associated with reduced recurrence-free survival. McAlhany SJ, Ayala GE, Frolov A, Ressler SJ, Wheeler TM, Watson JE, Collins C, Rowley DR. Prostate 2004; 61: 182-191. Medline 15305341

Molecular analysis of WFDC1/ps20 gene in prostate cancer. Watson JE, Kamkar S, James K, Kowbel D, Andaya A, Paris PL, Simko J, Carroll P, McAlhany S, Rowley D, Collins C. Prostate 2004;61:192-9. Medline 15305342

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire 2003 Updated 06- Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire 2005

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -218- Citation This paper should be referenced as such : Saffroy R, Lemoine A, Debuire B . WFDC1 (WAP four-disulfide core domain 1). Atlas Genet Cytogenet Oncol Haematol. March 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/WFDC1ID424.html Saffroy R, Lemoine A, Debuire B . WFDC1 (WAP four-disulfide core domain 1). Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/WFDC1ID424.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -219- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ELL (eleven nineteen lysin rich leukemia gene) (updated: old version not available)

Identity Other MEN (myeloid eleven nineteen translocation: <-- WARNING: names unrelated to MEN1 and MEN2); ELL-PEN Hugo ELL Location 19p13.1 proximal from LYL1 in 19p13.2-p13.1; ENL and E2A are more distal in

19p13.3 DNA/RNA Transcription alternate splicing; 4.4 and 2.8 kb mRNA; coding sequence: 1.9 kb Protein

Description 621 amino acids; 68 kDa; contains a Lysin rich domain (basic motif) Expression wide; especially in leukocytes, muscle, testis, placenta Localisation nuclear, except the nucleolus Function RNA polymerase II elongation factor, promotes transcription by suppressing transient pausings. In Drosophila ELL is associated with active sites of transcription in vivo. Overexpression of ELL is toxic, suggesting the normal protein may play a role in the regulation of cell growth and survival. Homology ELL2, ELL3 Implicated in Entity t(11.19)(q23;p13.1) /ANLL --> MLL-ELL Disease mainly M4/M5; treatment related leukemia; all ages Prognosis very poor Cytogenetics detected with R banding Hybrid/Mutated 5' MLL - 3' ELL Gene Abnormal Similar to other MLL fusion proteins. The amino terminal AT hook Protein and DNA methyltransferase homology regions from from MLL are fused to most of ELL Oncogenesis The carboxyl terminal region of ELL is required for transformation by MLL-ELL in murine bone marrow transformation assays. This region has potent transcriptional activating activity, and interacts with EAF1,

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -220- a protein that shares homology with AF4, LAF4, and AF5q31. Interestingly the EAF1 interacting domain, but not the ELL elongation domain is required for transformation. ELL has also been reported to interact withp53 and inhibit its transcriptional activating activity.

External links Nomenclature Hugo ELL GDB ELL Entrez_Gene ELL 8178 elongation factor RNA polymerase II Cards Atlas ELL GeneCards ELL Ensembl ELL CancerGene ELL Genatlas ELL GeneLynx ELL eGenome ELL euGene 8178 Genomic and cartography ELL - 19p13.1 chr19:18414475-18493918 - 19p13.11 (hg17- GoldenPath May_2004) Ensembl ELL - 19p13.11 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ELL Gene and transcription

Genbank AC005387 [ SRS ] AC005387 [ ENTREZ ]

Genbank AF157562 [ SRS ] AF157562 [ ENTREZ ]

Genbank AL136771 [ SRS ] AL136771 [ ENTREZ ]

Genbank BC010010 [ SRS ] BC010010 [ ENTREZ ]

Genbank BC033673 [ SRS ] BC033673 [ ENTREZ ]

RefSeq NM_006532 [ SRS ] NM_006532 [ ENTREZ ]

RefSeq NT_086897 [ SRS ] NT_086897 [ ENTREZ ] AceView ELL AceView - NCBI TRASER ELL Traser - Stanford

Unigene Hs.515260 [ SRS ] Hs.515260 [ NCBI ] HS515260 [ spliceNest ] Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -221- SwissProt P55199 [ SRS] P55199 [ EXPASY ] P55199 [ INTERPRO ]

Interpro IPR010844 Occludin_ELL [ SRS ] IPR010844 Occludin_ELL [ EBI ] CluSTr P55199

PF07303 Occludin_ELL [ SRS ] PF07303 Occludin_ELL [ Sanger Pfam ] pfam07303 [ NCBI-CDD ] Blocks P55199 Polymorphism : SNP, mutations, diseases OMIM 600284 [ map ] GENECLINICS 600284

SNP ELL [dbSNP-NCBI]

SNP NM_006532 [SNP-NCI]

SNP ELL [GeneSNPs - Utah] ELL [SNP - CSHL] ELL] [HGBASE - SRS] General knowledge Family ELL [UCSC Family Browser] Browser SOURCE NM_006532 SMD Hs.515260 SAGE Hs.515260 Amigo process|RNA elongation from Pol II promoter Amigo component|nucleus Amigo function|positive transcription elongation factor activity Amigo process|regulation of transcription, DNA-dependent PubGene ELL Other databases Probes Probe ELL Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography Cloning of ELL, a gene that fuses to MLL in a t(11;19)(q23;p13.1) in acute myeloid leukemia. Thirman MJ, Levitan DA, Kobayashi H, Simon MC, Rowley JD Proc Natl Acad Sci U S A 1994 Dec 6;91(25):12110-4 Medline 95083651

Cloning of several species of MLL/MEN chimeric cDNAs in myeloid leukemia with t(11;19)(q23;p13.1) translocation. Mitani K, Kanda Y, Ogawa S, Tanaka T, Inazawa J, Yazaki Y, Hirai H Blood 1995 Apr 15;85(8):2017-24 Medline 95235023

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -222-

An RNA polymerase II elongation factor encoded by the human ELL gene. Shilatifard A, Lane WS, Jackson KW, Conaway RC, Conaway JW Science 1996 Mar 29;271(5257):1873-6 Medline 96175588

Structure and function of RNA polymerase II elongation factor ELL. Identification of two overlapping ELL functional domains that govern its interaction with polymerase and the ternary elongation complex. Shilatifard A, Haque D, Conaway RC, Conaway JW J Biol Chem 1997 Aug 29;272(35):22355-63 Medline 97413851

Transcriptional inhibition of p53 by the MLL/MEN chimeric protein found in myeloid leukemia. Maki K, Mitani K, Yamagata T, Kurokawa M, Kanda Y, Yazaki Y, Hirai H. Blood. 1999 93(10):3216-24. Medline 99252074

Identification, cloning, expression, and biochemical characterization of the testis-specific RNA polymerase II elongation factor ELL3. Miller T, Williams K, Johnstone RW, Shilatifard A. J Biol Chemistry 2000 Oct 13 275(41):32052-6. Medline 20493588

A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. DiMartino JF, Miller T, Ayton PM, Landewe T, Hess JL, Cleary ML, Shilatifard A. Blood 2000 96(12):3887-93. Medline 20541523

Drosophila ELL is associated with actively elongating RNA polymerase II on transcriptionally active sites in vivo. Gerber M, Ma J, Dean K, Eissenberg JC, Shilatifard A. EMBO J 2001 20(21):6104-14. Medline 21547947

Functional analysis of the leukemia protein ELL: evidence for a role in the regulation of cell growth and survival. Johnstone RW, Gerber M, Landewe T, Tollefson A, Wold WS, Shilatifard A. Mol Cell Biol 2001 21(5):1672-81. Medline 21137189

EAF1, a novel ELL-associated factor that is delocalized by expression of the MLL-ELL fusion protein. Simone F, Polak PE, Kaberlein JJ, Luo RT, Levitan DA, Thirman MJ.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -223- Blood 2001 98(1):201-9. Medline 21311412

The elongation domain of ELL is dispensable but its ELL-associated factor 1 interaction domain is essential for MLL-ELL-induced leukemogenesis. Luo RT, Lavau C, Du C, Simone F, Polak PE, Kawamata S, Thirman MJ. Mol Cell Biol 2001 21(16):5678-87. Medline 21356990

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 12- Jean-Loup Huret 1997 Updated 04- Jay L. Hess 2003 Citation This paper should be referenced as such : Huret JL . ELL (eleven nineteen lysin rich leukemia gene). Atlas Genet Cytogenet Oncol Haematol. December 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ELL.html Hess JL . ELL (eleven nineteen lysin rich leukemia gene). Atlas Genet Cytogenet Oncol Haematol. April 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ELL.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -224- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(7;9)(q34;q34)

Clinics and Pathology Disease Specifically associated with T-cell Acute Lymphoblastic Leukemia (T- ALL). Note This translocation is related to Notch1 (TAN1) dysregulation. Mutation or chromosomal rearrangements of Notch gene have not yet been identified outside of T-ALL but Notch1 was recently studied by immunohistochemistry in various subsets of human lymphomas. Strong staining was found in Hodgkin¹s lymphoma (HL) and anaplastic large cell lymphoma (ALCL) but much additional works is needed to determine whether Notch signaling is necessary for HL and ALCL growth and survival. Phenotype / cell stem T lineage. CD4+ CD8+ double positive stage. origin Epidemiology Rare: < 1% among T-ALL. Cytogenetics Cytogenetics 9q34 is a partner of 7q34. The other partners are 1p34, 1p32, 9q32, Morphological 10q24, 11p13, 15q22, 19p13 Additional In T- lymphoblastic cell lines: polyploidy, inv(2)(p22;q11), anomalies inv(14)(q11;q32), del(6)(q23q27), del(4)(q13q35) Genes involved and Proteins Gene TCRB: T-cell receptor beta-chain gene on 7q35 Name Location 7q35 The TRB locus spans 685 Kb. The locus contains 2 types of coding elements : TCR elements (64-67 variable genes TRBV, 2 clusters of Dna / Rna diversity, joining and constant segments) and 8 trypsinogen genes. A portion of the TCRB locus has been duplicated and translocated to the chromosome 9 at 9p21. Protein T cell receptor beta chains. Gene NOTCH1 alias TAN1 (translocation-associated Notch homolog) Name Location 9q34.3

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -225- Note Notch receptors are highly conserved transmembrane glycoproteins that regulate the morphogenesis through a signaling pathway with pleiotropic effects of apoptosis, proliferation and cellular differenciation. At least one Notch homolog is expressed in human bone marrow CD34+ cells, on the basis of this finding, it is likely that members of Notch family, including TAN1, may be involved in mediating cell-fate decisions during hematopoiesis. Dna / Rna DNA size: 49715 bases Protein Size: 2256 amino acids, 272550 Da. Functions as a receptor for membrane-bound ligands Jagged1. Result of the chromosomal anomaly Hybrid The t(7;9) disrupts the Notch1 gene, fusing the 3¹end portion encoding gene its intracellular domain (ICN) to enhancer and promoter elements of the Description T cell receptor (TCRB). This results in overexpression of a constitutively active form of Notch activating genes that inhibit cell differenciation.The t(7;9)(q34;q34) results in a serie of tumor specific 5¹deleted Notch1 mRNA transcripts. All known beakpoints fall within a single intron in the coding sequence for the EGF repeat 34 of Notch1. The t(7 ;9) truncated transcripts encode ICN1-like polypetides (ICN = intracellular portion of Notch receptor). These polypeptides localize to the nucleus and structurally resemble ICN1. The intracellular portion of Notch1 contains six ankyrin repeats that are similar to those found in cytoplasmic I kappa B proteins or I kappa B are specific inhibitors of nuclear factor NFKappa B transcription factors.

Fusion On primary effect of constitutive Notch 1 activation is the maturation Protein arest of T lymphoblastes at the CD4+ CD8+ double positive stage but Oncogenesis recent works suggest that Notch contributes to T cell transformation by influencing proliferation and survival, rather than merely blocking differenciation.

External links Other t(7;9)(q34;q34) Mitelman database (CGAP - NCBI) database Other t(7;9)(q34;q34) CancerChromosomes (NCBI) database Bibliography Clinical and biologic characterization of T-cell Neoplasias with rearrangements of chromosome 7 band q34. Smith S, Morgan R, Gemmell R , Amylon M, Link M, Linker C, Hecht B, Warnke R, Hecht F. Blood 1988 ; 71(2): 395-402 Medline 2962650

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -226-

TAN-1 the human homolog of the Drosophilia notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, SKLAR J. Cell 1991; 66(4) : 649-661 Medline 1831692

Karyotype and T-cell receptor expression in T-lineage acute lymphoblastic leukemia. Secker-Walker LM, Campana D, Hawkins JM, Sampson RE, Coustan-Smith E. Genes Chromosomes Cancer 1992; 4(1): 41-45 Medline 1377008

A human homologue of the drosophilia developmental gene, Notch is expressed in CD34+ hematopoietic precursors. Milner LA, Kopan R, Martin DI, Berstein ID. Blood 1994; 83(8) : 2057-2062 Medline 7512837

Cytogenetic abnormalities in adult acute lymphoblastic leukemia : correlations with hematologic findings outcome. A collaborative Study of the Groupe Français de Cytogénétique Hématologique. Groupe Français de Cytogénétique Hématologique. Blood 1996; 87(8) : 3135-3142 Medline 8605327

T cell leukemia-associated human Notch homologue has I Kappa B-like activity and physically interacts with nuclear-factor-kappa B proteins in T cells. Guan E, Wang J, Laborda J, Norcross M, Baeuerle PA, Hoffman T. J Exp Med 1996 ; 183(5) : 2025-2032 Medline 8642313

Essential roles for ankyrin repeats as transactivation domains in induction of T cell leukemia by Notch1. Aster JC, Xu l, Karnell FG, Patriub V, Pui JC, Pear WS. Molecular and Cellular Biology 2000; 20(20) : 7505-7515 Medline 11003647

Neoplastic transformation by Notch requires nuclear localization. Jeffries S, Capabianco AJ. Mol Cell Biol 2000; 20(11) : 3928-3941 Medline 10805736

Notch signaling in cancer. Allenspach EJ, Maillard I, Aster JC, Pear WS. Cancer biology and therapy 2001 in press

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -227-

Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, Behm F, Pui CH, Downing JR, Gilliland DG, Lander ES, Golub TR, Look AT. Cancer Cell 2002; 1(1): 75-87 Medline 12086890

Contributor(s) Written 01- Jacques Boyer 2003 Citation This paper should be referenced as such : Boyer J . t(7;9)(q34;q34). Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0709q34q34ID1055.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -228- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(7;19)(q34;p13)

Identity Note Non random translocations involving the short arm of chromosome 19 are observed in acute leukemia. The 19p13 genes E2A and LYL1 (see below) lie at two different translocation breakpoints in acute lymphoblastic leukemia. For instance the E2A gene is involved in the t(1;19)(q23 ;p13) in acute pre-B leukemia (B-ALL) and the LYL1 gene is structurally altered in the t(7;19)(q34 ;p13) in T cell leukemia (T-ALL). Clinics and Pathology Disease Specifically associated with T-cell Acute lymphoblastic leukemia (T- ALL) Phenotype / Recents works, using oligonucleotide microarrays, show that several cell stem gene expression signatures are indicative of leukemic arrest at specific origin stages of normal thymocyte development : LYL1 signature : pro-T (CD34+ CD3- CD4- CD8- CD1a-) HOX11 ID 31>: early cortical thymocyte and TAL1 late cortical thymocyte. LYL1 positivity is related to higher expression levels of the MYCN, LMO2 and PLZF proto-oncogenes as well as the antiapoptotic gene . PHENOTYPE_STEM_CELL_ORIGIN These findings have clinical importance (see Prognosis) Epidemiology Rare : < 1% among T-ALL. The t(7;9)(q34;q32) is present in one case of a serie of 5 patients with 7q34 involvment. Prognosis HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1 and surprisingly HOX11L2 confers a much worse response to treatment. The upregulation of BCL2 may explain their relative resistance to chemotherapy. Cytogenetics Cytogenetics 19p13 is a partner of 7q34. The other partners are 1p34,1p32, Morphological 9q34,9q32,10q24,11p13, 15q22. Genes involved and Proteins Gene TCRB (T-cell receptor beta-chain gene) Name Location 7q35 Dna / Rna The TRB locus at 7q35 spans 685 Kb. The locus contains 2 types of

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -229- coding elements : TCR elements (64-67 variable genes TRBV, 2 clusters of diversity, joining and constant segments) and 8 trypsinogen genes. Protein T cell receptor beta chains. Gene LYL1 Name Location 19p13.2-p13.1 Note The LYL1 gene is assigned to 19p13.2-p13.1 by fluorescence in situ hybridation. An RNA of about 1.5 kb is transcribed from this gene in a wide variety of Dna / Rna lymphoid cell lines with the notable exception of thymocytes and T cells. Protein LYL1 encodes a basic helix-loop-helix (bHLH) phosphoprotein (size 108 amino acids) that is highly. Related to TAL1 : TAL1 and LYL1 HLH proteins show an 87% level of aminoacid identity. Result of the chromosomal anomaly Hybrid The LYL1 gene is structurally altered following the t(7;19) translocation, gene resulting in its head-to-head juxtaposition with the T cell receptor beta Description gene. In the human T cell line SUP-T7 established from an acute lymphoblastic leukemia, nucleotide sequence analysis showed that the point of crossover on chromosome 7 occured immediately adjacent to joining segment beta 1.1 within the TCR beta gene, suggesting that this translocation resulted from an error in TCR gene rearrangement. The t(7;19) resulted in truncation of the LYL1 gene and production of abnormal-sized RNAs suggesting a role for LYL1 in the pathogenesis of T Leukemia.

Fusion Several helix-loop-helix (HLH) proteins are proposed to function as Protein transcriptionnal regulatory factors based on their ability to bind in vitro Oncogenesis the E-box motif of transcriptional enhancers. The enhancer binding HLH proteins include E47 and E12, two distinct but related polypeptides encoded by E2A gene that are able to form heterologous complexes with other HLH proteins like TAL1 and LYL1 polypeptides. Thus LYL1 may function as a dominant-negative mutant preventing the activation of E2A responsive genes. It is plausible that the inactivation of E2A target genes is an essential and common step toward the development of a number of T-cell malignancies. LYL1 interacts also with p105 the precursor of NF-KappaB1 p50. Biochemical studies indicate that this interaction is mediated by the HLH motif of LYL1 and the ankyrin-like motifs of p105. Ectopic expression of LYL1 cause a significant decrease in NF- KappaB- dependant transcription associated with a reduced level of NF-KappaB-dependant proteins.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -230- External links Other t(7;19)(q34;p13) Mitelman database (CGAP - NCBI) database Other t(7;19)(q34;p13) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Clinical and biologic characterization of T-cell Neoplasias with rearrangements of chromosome 7 band q34. Smith S, Morgan R, Gemmell R, Amylon M, Link M, Linker C, Hecht B, Warnke R, Hecht F Blood 1988; 71(2): 395-402

LYL1 a novel gene altered by chromosomal translocation in T cell leukemia, codes for a protein with a helix-loop-helix DNA binding motif. Mellentin JD, Smith SD, Cleary ML. Cell 1989 14; 58(1): 77-83 Medline 2752424

TAL1, TAL2 and LYL1 : a family of basic helix-loop-helix proteins implicated in T cell acute leukemia. Baer R. Semin Cancer Biol 1993; 4(6): 341-347 Medline 8142619

Fluorescence in situ hybridation mapping of human chromosome 19 : cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Trask B, Fertitta A, Christensen M, Youngblom J, Bergmann A, Copeland A, De Jong P, Mohrenweiser H, Olsen A, Carrana A, Tynan K. Genomics 1993; 15: 133-145 Medline 8432525

Cytogenetic abnormalities in adult acute lymphoblastic leukemia : correlations with hematologic findings outcome. A collaborative Study of the Groupe Fran ais de CytogŽnŽtique HŽmatologique.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -231- GFCH Blood 1996; 87(8): 3135-3142 Medline 8605327

Helix loop helix proteins LYL1 and E2A form heterodimeric complexes with distinctive DNA binding properties in hematolymphoid cells. Miyamoto A, Cui X, Naumovski L, Cleary ML. Mol Cell Biol 1996; 16(5): 2394-2401 Medline 8628307

E2A deficiency leads to abnormalities in alpha beta T-Cell development and to rapid development of T-Cell Lymphomas Bain G, Engel I, Maandag R, Voland J, Sharp L, Chun J, Murre C. Mol Cell Biol 1997; 17(8): 4782-4791. Medline 9234734

Physical interaction of the bHLH LYL1 protein and NF-KappaB1 p105 Ferrier R, Nougarede R, Doucet S, Kahn-Perles B, Imbert J, Mathieu Mahul D. Oncogene 1999; 18(4): 995-1005 Medline 10023675

Contributor(s) Written 01- Jacques Boyer 2003 Citation This paper should be referenced as such : Boyer J . t(7;19)(q34;p13). Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0719q34p13ID1060.html

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3q rearrangements in myeloid malignancies

Identity

Clinics and Pathology Disease In myeloid malignancies (acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myelogenous leukemia (CML) as well as other myeloproliferative disorders), involvement of 3q26 in balanced rearrangements is highly suggestive of EVI1 and/or MDS1/EVI1 rearrangement. As a consequence, balanced aberrations involving 3q26 are mainly detected in myeloid malignancies. Epidemiology 3q26 rearrangements have been described in up to 5% of unselected patients with myeloid malignancies. Clinics Often associated with young age at diagnosis, trilineage dysplasia, dysmegakaryopoiesis and prior treatment with alkylating agents. Evolution In CML, emergence of an additional Ph+ clone with a 3q26 rearrangement can be indicative of a pending disease transformation. Prognosis Generally 3q26 rearrangements are associated with adverse prognosis. This adverse prognosis probably correlates to the highly increased EVI1 expression, detectable in the vast majority of these patients. Whether 3q26 rearrangements, which are not associated with ectopic EVI1 expression share the same prognostic features, however, has not been addressed. Cytogenetics Cytogenetics Although the frequently occurring balanced 3q26 rearrangements can Morphological be readily identified by G-, Q-, or R-banding, the distal localisation makes it a good candidate for involvement in cryptic aberrations. Rearrangements in which EVI1 and or MDS1/EVI1 involvement have been well established include: CYTOGENETICS_MORPHOL t(3;3)(q21;q26) inv(3)(q21q26)

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -233- ins(3)(q26;q21q26) t(3;12)(q26;p13) t(3;21)(q26;q22)

Recently we demonstrated EVI1 involvement in other recurrent rearrangements such as :

t(2;3)(p13-p23;q26) t(3;6)(q26;q25). t(3;13)(q26;q14) t(3;17)(q26;q22)

In addition, EVI1 is involved in more rare rearrangements such as

inv(3)(p12q26) inv(3)(q23q26) t(3;3)(p24;q26) t(3;5)(q26;q34) t(3;9)(q26;p23) t(3;12)(q26;q21) t(3;18)(q26;q11).

One should be aware of the fact, however, that in the majority of patients demonstrating ectopic EVI1 expression, 3q26 rearrangements are generally not detectable cytogenetically. Whether in these patients cryptic aberrations cause EVI1 deregulation is currently under investigation. Cytogenetics Breakpoint heterogeneity, with breakpoints mapping 3Õ as well as 5Õ, Molecular of EVI1 impeded a sensitive detection of EVI1 rearrangement using molecular cytogenetic techniques. Recently, however, we studied numerous 3q26 rearrangements using a 1.3Mb contig covering the EVI1 locus. We demonstrated sensitive and specific detection of EVI1 rearrangements using dual colour FISH using the following probe combinations: RP11-82C9 and RP11-694D5 for 5Õ rearrangements and RP11-82C9 and RP11-362K14 for 3Õ rearrangements. Additional 3q26 rearrangements are frequently associated with monosomy 7 and anomalies complex chromosomal aberrations. Genes involved and Proteins Gene EVI1, MDS1/EVI1 and MDS1 Name Location 3q26.2 Note EVI1 and MDS1 display intergenic splicing, creating a PR domain member, MDS1/EVI1. Analogously to other PR domain genes, such as RIZ, MDS1/EVI1 and EVI1 are hypothesised to display antagonistic properties. Currently, experimental data are limited and conflicting indicating that further experiments are needed to clarify the exact role of

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -234- both evolutionary conserved transcripts. The different transcripts encoded by the EVI1 locus.

EVI1 spans approximately 50 kb and contains 12 exons, 10 of which are coding. Translation starts in exon 3. MDS1/EVI1 results from intergenic splicing from MDS1 and EVI1, the Dna / Rna resulting transcript MDS1/EVI1, contains the 2 first MDS1 exons spliced in frame to EVI1 exon 2. The MDS1 gene spans approximately 230kb. Protein The EVI1 gene encodes a sequence specific Cys2/Hys2 type 145kDa zinc finger protein, containing two sets of seven and three zing fingers, respectively. Alternative splicing creates a 88 kDa isoform that lacks the nuclear localisation signal and two zinc fingers. MDS1/EVI1 encodes a PR domain family member. The PR domain is suggested to play an inhibiting role in tumorigenesis. Result of the chromosomal anomaly Hybrid Ectopic expression of an intact or truncated EVI1 transcript has been gene Note reported as a result of 3q26 rearrangements. Generally, 3q26 breakpoints map 3' to EVI1 in the inv(3) while the t(3;3) breakpoints more frequently reside 5' to EVI1. In addition expression of GR6/EVI1 and RPN1/EVI1 chimeras have been described in the t(3;3). Alternatively, AML1/MDS1, AML1/MDS1/EVI1 and AML1/EVI1 fusion transcripts are produced by the t(3;21)(q26;q22), while ETV6/MDS1/EVI1 and ETV6/EVI1 fusions are related to the t(3;12)(q26;p13). The net effect of these rearrangements comprises an EVI1 gain of function: as a result of EVI1 ectopic expression or resulting from MDS1/EVI1 inactivation by disruption of its PR domain.

Several hybrid genes resulting from 3q26 rearrangements have been characterised and cloned, including the AML1/MDS1/EVI1 from the t(3;21)(q26;q22) and the ETV6/MDS1/EVI1 in the t(3;12)(q26;p13) these rearrangements are discussed elsewhere in the Atlas.

External links (AC078985) Probe

(AC112911) Probe

(AC078795) Probe

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -235-

Bibliography Retroviral activation of a novel gene encoding a zinc finger protein in IL-3- dependent myeloid leukemia cell lines. Morishita K, Parker DS, Mucenski ML, Jenkins NA, Copeland NG, Ihle JN Cell 1988; 54: 831-840. Medline 88311086

Identification of a common ecotropic viral integration site, Evi-1, in the DNA of AKXD murine myeloid tumors. Mucenski ML, Taylor BA, Ihle JN, Hartley JW, Morse HC, 3rd, Jenkins NA, Copeland NG Mol Cell Biol 1988; 8: 301-308. Medline 88094400

Identification, nuclear localization, and DNA-binding activity of the zinc finger protein encoded by the Evi-1 myeloid transforming gene. Matsugi T, Morishita K, Ihle JN. Mol Cell Biol 1990; 10: 1259-1264. Medline 90158592

Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300-400 kilobases on chromosome band 3q26. Morishita K, Parganas E, William CL, Whittaker MH, Drabkin H, Oval J, Taetle R, Valentine MB, Ihle JN. Proc Natl Acad Sci U S A 1992; 89: 3937-3941. Medline 92237284

Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H, Yazaki Y, Ohki M, Hirai H. Embo J 1994; 13: 504-510. Medline 94147997

Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. Russell M, List A, Greenberg P, Woodward S, Glinsmann B, Parganas E, Ihle J, Taetle R. Blood 1994; 84: 1243-1248. Medline 94325569

Identification of a breakpoint cluster region 3' of the ribophorin I gene at 3q21 associated with the transcriptional activation of the EVI1 gene in acute myelogenous leukemias with inv(3)(q21q26). Suzukawa K, Parganas E, Gajjar A, Abe T, Takahashi S, Tani K, Asano S, Asou H,

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -236- Kamada N, Yokota J and et al. Blood 1994; 84: 2681-2688. Medline 95002989

Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family. Fears S, Mathieu C, Zeleznik-Le N, Huang S, Rowley JD, Nucifora G Proc Natl Acad Sci U S A 1996; 93: 1642-1647. Medline 96202331

Molecular analysis of Evi1, a zinc finger oncogene involved in myeloid leukemia. Lopingco MC, Perkins AS. Curr Top Microbiol Immunol 1996; 211: 211-222. Medline 96148172

The Evi1 proto-oncogene is required at midgestation for neural, heart, and paraxial mesenchyme development. Hoyt PR, Bartholomew C, Davis AJ, Yutzey K, Gamer LW, Potter SS, Ihle JN, Mucenski ML Mech Dev 1997; 65: 55-70. Medline 97398447

The EVI1 gene in myeloid leukemia. Nucifora G. Leukemia 1997; 11: 2022-2031. (REVIEW) Medline 98107504

Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Peeters P, Wlodarska I, Baens M, Criel A, Selleslag D, Hagemeijer A, Van den Berghe H, Marynen P. Cancer Res 1997; 57: 564-569. Medline 97178925

Activation of a novel gene in 3q21 and identification of intergenic fusion transcripts with ecotropic viral insertion site I in leukemia. Pekarsky Y, Rynditch A, Wieser R, Fonatsch C, Gardiner K. Cancer Res 1997; 57: 3914-3919. Medline 97450830

The leukemia-associated gene MDS1/EVI1 is a new type of GATA-binding transactivator Soderholm J, Kobayashi H, Mathieu C, Rowley JD, Nucifora G Leukemia 1997; 11: 352-358. Medline 97220198

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Human AML1/MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: a model for human AML. Cuenco GM, Nucifora G, Ren R Proc Natl Acad Sci U S A 2000; 97: 1760-1765. Medline 20144114

High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S, Hack R, Slater R, Smit EM, Beverloo HB, Verhoef G, Verdonck LF, Ossenkoppele GJ, Sonneveld P, de Greef GE, Lowenberg B, Delwel R. Blood 2003; 101: 837-845. Medline 22417151

Quantitative comparison of the expression of EVI1 and its presumptive antagonist, MDS1/EVI1, in patients with myeloid leukemia. Vinatzer U, Mannhalter C, Mitterbauer M, Gruener H, Greinix H, Schmidt H, Fonatsch C, Wieser R. Genes Chromosomes Cancer 2003; 36: 80-89. Medline 22349520

High resolution molecular cytogenetics and MDS1, MDS1/EVI1 and EVI1 expression patterns in rearrangements involving 3q26. Poppe B, Dastugue N, De Smet B, Yigit N, De Paepe A, Recher C, De Mas V, Hagemeijer A, Speleman F. In preparation

Contributor(s) Written 02- Bruce Poppe, Nicole Dastugue, Frank Speleman 2003 Citation This paper should be referenced as such : Poppe B, Dastugue N, Speleman F. . 3q rearrangements in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/3qrearrmyeloID1125.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -238- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(2;21)(p11;q22)

Clinics and Pathology Disease M1 acute non lymhocytic leukemia (ANLL) Etiology no known prior exposure Epidemiology only one case to date, a 78 yr old male patient Prognosis death occurred during induction therapy Cytogenetics Cytogenetics sole anomaly in this patient Morphological Genes involved and Proteins Note The gene in 2p11 is yet unknown, and, because cryptic t(12;21) ETV6 /AML1 are not rare, it is therefore uncertain whether this translocation involve a new AML1 partner Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes External links Other t(2;21)(p11;q22) Mitelman database (CGAP - NCBI) database Other t(2;21)(p11;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Identification of two new translocations that disrupt the AML1 gene.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -239- Richkind K, Hromas R, Lytle C, Crenshaw D, Velasco J, Roherty S, Srinivasiah J, Varella-Garcia M. Cancer Genet Cytogenet 2000; 122: 141-143. Medline 11106827

Contributor(s) Written 02- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(2;21)(p11;q22). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0221p11q22ID1261.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -240- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(4;21)(q31;q22)

Clinics and Pathology Disease T-cell acute lymphoblastic leukemia (T-ALL) Epidemiology only one case to date, a 12 yr old male patient Prognosis unknown Cytogenetics Cytogenetics a del(7q) was also present in the same clone Morphological Genes involved and Proteins Note The gene in 4q31 is yet unknown, and, because cryptic t(12;21) ETV6 /AML1 are not rare, it is therefore uncertain whether this translocation involve a new AML1 partner Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes External links Other t(4;21)(q31;q22) Mitelman database (CGAP - NCBI) database Other t(4;21)(q31;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Novel cryptic, complex rearrangements involving ETV6-CBFA2 (TEL-AML1) genes identified by fluorescence in situ hybridization in pediatric patients with

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -241- acute lymphoblastic leukemia. Mathew S, Shurtleff SA, Raimondi SC. Genes Chromosomes Cancer. 2001; 32: 188-193. Medline 11550288

Contributor(s) Written 02- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(4;21)(q31;q22). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0421q31q22ID1262.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -242- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(5;21)(q13;q22)

Clinics and Pathology Disease myelodysplastic syndrome (MDS) and acute non lymphocytic leukemia (ANLL) Phenotype / 1 case of refractory anemia with excess of blastsin transformation cell stem (RAEB-t), 1 MDS evolving towards a M4-ANLL, 2 M2-ANLL, and 1 origin ANLL not otherwise specified Epidemiology 5 cases to date; 3M/2F, aged 58 yr (median, range: 31-75) Cytogenetics Cytogenetics sole anomaly in 2 cases, complex karyotypes in 2 other cases. Morphological Genes involved and Proteins Note The gene in 5q13 is yet unknown, and, because cryptic t(12;21) ETV6 /AML1 are not rare, it is therefore uncertain whether this translocation involve a new AML1 partner Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes External links Other t(5;21)(q13;q22) Mitelman database (CGAP - NCBI) database Other t(5;21)(q13;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -243- Chromosome pattern, occupation, and clinical features in patients with acute non-lymphocytic leukemia. Mitelman F, Nilsson PG, Brandt L, Alimena G, Gastaldi R, Dallapiccola B. Cancer Genet Cytogenet 1981; 4: 197-214.

A new translocation, t(5;21)(q13;q22) in acute myelogenous leukemia. Gogineni SK, da Costa M, Verma RS. Cancer Genet Cytogenet 1996; 88: 167-169.

CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. Roulston D, Espinosa III R, Nucifora G, Larson RA, Le Beau MM, Rowley JD. Blood 1998; 92:2879-2885.

Testicular infiltration in acute myeloid leukemia with complex karyotype including t(8;21). Giagounidis AAN, Hildebrandt B, Braunstein S, Aivado M, Germing U, Heinsch M, Aul C. Ann Hematol 2002; 81: 115-118

Contributor(s) Written 02- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(5;21)(q13;q22). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0521q13q22ID1174.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -244- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(6;21)(p22;q22)

Clinics and Pathology Disease Treatment related myelodysplastic syndrome (refractory anemia with excess of blasts: RAEB) Etiology RAEB occurred 60 w after diagnosis of an acute lymphoblastic leukemia treated with topoisomerase II inhibitors Epidemiology only one case to date, a 4 yr old female patient Prognosis the patient died 10 mths after diagnosis Cytogenetics Cytogenetics a t(2;11)(p23;q23) with MLL involvement was also present in the same Morphological clone Genes involved and Proteins Note The gene in 6p22 is yet unknown, and, because cryptic t(12;21) ETV6 /AML1 are not rare, it is therefore uncertain whether this translocation involve a new AML1 partner Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes External links Other t(6;21)(p22;q22) Mitelman database (CGAP - NCBI) database Other t(6;21)(p22;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -245- Bibliography Concurrent translocations of MLL and CBFA2 (AML1) genes with new partner breakpoints in a child with secondary myelodysplastic syndrome after treatment of acute lymphoblastic leukemia. Mathew S, Head D, Rubnitz JE, Raimondi SC. Genes Chromosomes Cancer 2000; 28: 227-232. Medline 10825008

Contributor(s) Written 02- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(6;21)(p22;q22). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0621p22q22ID1266.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -246- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(8;21)(q24;q22)

Clinics and Pathology Disease T-cell acute lymphoblastic leukemia (ALL) and acute non lymhocytic leukemia (ANLL) Phenotype / cell stem 1 case of T-cell ALL and 2 cases of ANLL, one of which was a M4 origin Epidemiology 2 documented cases, male patients aged 5 yrs (ALL case) and 42 yrs (ANLL case) Cytogenetics Cytogenetics +21 (ALL case); complex karyotype (ANLL case) Morphological Genes involved and Proteins Note this translocation may be heterogeneous at the molecular level, as it is concerning the phenotype Gene TRPS1 Name Location 8q24 Protein transcriptional repressor Germinal involved in tricho-rhino-phalangeal syndrome mutations Somatic involved with AML1in the M4-ANLL case mutations Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes External links Other t(8;21)(q24;q22) Mitelman database (CGAP - NCBI) database

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -247- Other t(8;21)(q24;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Abnormalities of chromosome 1 in relation to human malignant diseases. Olah E, Balogh E, Kovacs I, Kiss A. Cancer Genet Cytogenet 1989; 43:179-194.

Clinical significance of TAL1 gene alteration in childhood T-cell acute lymphoblastic leukemia and lymphoma. Kikuchi A, Hayashi Y, Kobayashi S, Hanada R, Moriwaki K, Yamamoto K, Fujimoto J, Kaneko Y, Yamamori S. Leukemia 1993; 7: 933-938.

AML1-TRPS1 chimeric protein is generated by t(8;21)(q24;q22) in relapsing acute myeloblastic leukemia. Asou N, Matsuno N, Mitsuya H. Am Soc Hematol, 43 Annual meeting, Blood 2001; 98 11: 564a.

Structure and fonction of GC79/TRPS1, a novel androgen-repressible apoptosis gene. Chang GT,van den Bemd GJ, Jhamai M, Brinkmann AO. Apoptosis 2002; 7: 13-21. Medline 11773701

Contributor(s) Written 02- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(8;21)(q24;q22). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0821q24q22ID1263.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -248- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(12;21)(q24;q22)

Clinics and Pathology Disease acute non lymphocytic leukemia (ANLL) Etiology may be treatment related Epidemiology only one case to date, a 66 yr old male patient Cytogenetics Cytogenetics sole anomaly in this patient Morphological Genes involved and Proteins Note The gene in 12q24 is yet unknown, and, because cryptic t(12;21) ETV6 /AML1 are not rare, it is therefore uncertain whether this translocation involve a new AML1 partner Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes External links Other t(12;21)(q24;q22) Mitelman database (CGAP - NCBI) database Other t(12;21)(q24;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography CBFA2(AML1) Translocations With Novel Partner Chromosomes in Myeloid Leukemias: Association With Prior Therapy.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -249- Roulston D, Espinosa IIIR, Nucifora G, Larson RA, Le Beau MM, Rowley JD. Blood 1998; 92: 2879-2885.

Contributor(s) Written 02- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(12;21)(q24;q22). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1221q24q22ID1268.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -250- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(14;21)(q22;q22)

Clinics and Pathology Disease Treatment related myelodysplastic syndrome (MDS) evolving towards acute non lymphocytic leukemia Etiology the patient experienced a Hodgkin disease 36 mths before diagnosis of MDS Epidemiology only one case to date, a 38 yr old male patient Cytogenetics Cytogenetics complex karyotype, including a del(5q) Morphological Genes involved and Proteins Note The gene in 14q22 is yet unknown, and, because cryptic t(12;21) ETV6 /AML1 are not rare, it is therefore uncertain whether this translocation involve a new AML1 partner Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes External links Other t(14;21)(q22;q22) Mitelman database (CGAP - NCBI) database Other t(14;21)(q22;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -251- CBFA2(AML1) Translocations With Novel Partner Chromosomes in Myeloid Leukemias: Association With Prior Therapy. Roulston D, Espinosa IIIR, Nucifora G, Larson RA, Le Beau MM, Rowley JD. Blood 1998; 92: 2879-2885. Medline 9763573

Contributor(s) Written 02- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(14;21)(q22;q22). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1421q22q22ID1269.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -252- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(15;21)(q22;q22)

Clinics and Pathology Disease Treatment related myelodysplastic syndrome (MDS) evolving towards acute non lymphocytic leukemia Etiology the patient experienced a mantle cell lymphoma 52 mths before diagnosis of MDS Epidemiology only one case to date, a 56 yr old male patient Cytogenetics Cytogenetics sole anomaly Morphological Genes involved and Proteins Note The gene in 15q22 is yet unknown, and, because cryptic t(12;21) ETV6 /AML1 are not rare, it is therefore uncertain whether this translocation involve a new AML1 partner Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes External links Other t(15;21)(q22;q22) Mitelman database (CGAP - NCBI) database Other t(15;21)(q22;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -253- CBFA2(AML1) Translocations With Novel Partner Chromosomes in Myeloid Leukemias: Association With Prior Therapy. Roulston D, Espinosa IIIR, Nucifora G, Larson RA, Le Beau MM, Rowley JD. Blood 1998; 92: 2879-2885. Medline 9763573

Contributor(s) Written 02- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(15;21)(q22;q22). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1521q22q22ID1270.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -254- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(20;21)(q13;q22)

Clinics and Pathology Disease refractory anemia with excess of blasts and M5- acute non lymphocytic leukemia Etiology tretment of a non Hodgkin lymphoma 2 yrs before diagnosis in 1 case Epidemiology only 2 male patient cases, aged 38 yrs and 69 yrs Cytogenetics Cytogenetics Complex karyotypes in 1 case, +10 in the other one Morphological Genes involved and Proteins Note The gene in 20q13 is yet unknown, and, because cryptic t(12;21) ETV6 /AML1 are not rare, it is therefore uncertain whether this translocation involve a new AML1 partner Gene AML1 Name Location 21q22 Dna / Rna transcription is from telomere to centromere Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes External links Other t(20;21)(q13;q22) Mitelman database (CGAP - NCBI) database Other t(20;21)(q13;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -255- Cancer Cytogenetic Group study. Secker-Walker LM, Mehta A, Bain B, UKCCG. Br J Haematol 1995; 91:490-501. Medline 8547101

Contributor(s) Written 02- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(20;21)(q13;q22). Atlas Genet Cytogenet Oncol Haematol. February 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t2021q13q22ID1264.html

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Bone: Adamantinoma

Identity Note Adamantinoma of long bones is a low-grade, malignant biphasic tumor, characterized by a variety of morphological patterns, most commonly epithelial cells, surrounded by a relatively bland spindle-cell osteofibrous component. Clinics and Pathology Etiology Cumulating evidence indicates that classic adamantinomas derive from their osteofibrous dysplasia (OFD)-like counterparts.OFD and adamantinoma show common cytogenetic abnormalities (see below), and by immunohistochemistry, it has been shown that the epithelial component of adamantinoma is directly derived from the fibrous tissue. However, clinical aggressiveness among OFD, OFD-like adamantinoma and classic adamantinoma varies considerably, and many OFD-like lesions may never progress to classic adamantinoma. Epidemiology Adamantinomas are rare, they comprise 0.1-0.5% of primary bone tumors. The peak incidence is in the second and third decade. The youngest age group (up to 15 years) mainly includes patients with osteofibrous dysplasia (OFD)-like adamantinoma, whereas in older patients classic adamantinomas are predominant. Clinics At conventional radiography, typically a well-circumscribed, central or eccentric, (multi-)lobulated osteolytic lesion is seen. Multifocality in the tibia as well as ipsilateral fibula is regularly observed. MRI is essential for pre-operative staging of the tumor and planning surgical margins. The treatment for most cases wide en-bloc resection. Adamantinomas may display a protracted clinical behavior. Some tumors have radiologically proven to be present 30 years prior to histological diagnosis, whereas metastases may occur decades after local treatment. Recurrence rate after irradical surgery may be as high as 90%, whereas up to 25% of these patients may develop metastases. Pathology Two main subtypes of adamantinoma are recognized: OFD-like adamantinomas lack a clear histological epithelial component, and mainly consist of osteofibrous tissue, in which woven bone trabeculae are rimmed by osteoblasts. Keratin immunohistochemistry highlights individual or small aggregates of positive cells. Classic adamantinomas have abundant epithelium, which may be arranged in basaloid, tubular, squamoid, spindle-cell, of mixed differentiation. Recently, sarcomatous dedifferentiation of the epithelial component

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Figure 1: Classic adamantinoma, hematoxylin and eosin, x 100. Strings of epithelial cells embedded in fibrous tissue. Figure 2: OFD-like adamantinoma, HE x 100. No epithelial cells are distinguishable in osteofibrous tissue. Figure 3: OFD-like adamantinoma, immunohistochemistry for pankeratin, x 100. Individual keratin-positive cells (same case as figure 2).

Cytogenetics Cytogenetics With DNA flow and image cytometry it was shown that about 40% Morphological (6 of 15) of adamantinomas were aneuploid, all of them classic adamantinomas, and most of them near diploid. The aneuploid population was always restricted to the epithelial component. p53-Protein accumulation was shown by immunohistochemistry (IHC) in 48% (12 of 25) adamantinomas, all classic subtype. LOH at the p53 locus was confirmed in DNA-sorted nuclei of epithelial cells in an IHC-positive tumor. Cytogenetic analysis by GTG-banding is restricted to 15 cases of adamantinoma (n=11) and OFD (n=4) in literature. OFD and the fibrous and epithelial component of adamantinoma show comparable numerical chromosomal abnormalities, mainly involving trisomies of chromosomes 7, 8, 12, 19 and 21. These findings further substantiate the clonal origin of OFD and the common histogenesis of OFD and adamantinoma. The finding of translocations, deletions, and inversions is common but not structural, and only present in adamantinomas. This suggests that expansion of an abnormal clone to include structural changes may parallel progression from OFD to adamantinoma. One young patient with classic adamantinoma had a constitutional t(7;13)(q32;q14), also present in his father. In literature some cases have been described with histological features of both Ewing's sarcoma and adamantinoma, sometimes called 'atypical' of 'Ewing-like' adamantinoma. Ewing's sarcoma is characterized by a t(11;22)(q24;q12). In one study on 3 archival cases with epithelial features, originally described as adamantinoma or non- typical Ewing's sarcoma (of which two were not located in the tibia), it was shown by FISH and RT-PCR that all had the typical t(11;22). They were therefore named 'adamantinoma-like' Ewing's sarcoma. Additionally, using RT-PCR on archival tissue, a t(11;22) or t(21;22) was not found in any of 12 informative adamantinomas. These data indicate that tumors showing overlapping morphological and immunohistochemical features can be readily distinguished with these techniques. Bibliography Adamantinoma of long bone. An analysis of nine new cases with emphasis on metastasizing lesions and fibrous dysplasia-like changes. Weiss SW, Dorfman HD. Hum Pathol 1977; 8: 141-153. Medline 852865

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Adamantinoma of the appendicular skeleton--updated. Moon NF, Mori H. Clin Orthop 1986; 204: 215-237. Medline 3514033

Morphologic diversity of long bone adamantinoma. The concept of differentiated (regressing) adamantinoma and its relationship to osteofibrous dysplasia. Czerniak B, Rojas-Corona RR, Dorfman HD. Cancer 1989; 64: 2319-2334. Medline 2804923

Fibrous dysplasia vs adamantinoma of the tibia. Differentiation based on discriminant analysis of clinical and plain film findings. Bloem JL, Van der Heul RO, Schuttevaer HM, Kuipers D. Am J Roentgenol 1991; 156: 1017-1023. Medline 2017924

Cortical osteofibrous dysplasia of long bone and its relationship to adamantinoma: A clinicopathologic study of 30 cases. Sweet DE, Vinh TN, Devaney K. Am J Surg Pathol 1992; 16: 282-290. Medline 1599019

Adamantinoma of the long bones: keratin subclass immunoreactivity pattern with reference to its histogenesis. Hazelbag HM, Fleuren GJ, Van den Broek LJCM, Taminiau AHM, Hogendoorn PCW. Am J Surg Pathol 1993; 17: 1225-1233. Medline 7694513

Clonal chromosomal abnormalities in osteofibrous dysplasia. Implications for histopathogenesis and its relationship with adamantinoma. Bridge JA, Dembinski A, DeBoer J, Travis J, Neff JR. Cancer 1994;73:1746-1752. Medline 8156503

Adamantinoma of long bones. A clinicopathological study of thirty-two cases with emphasis on histological subtype, precursor lesion and biological behavior. Hazelbag HM, Taminiau AHM, Fleuren GJ, Hogendoorn PCW. J Bone Joint Surg [Am] 1994; 76A: 1482-1499. Medline 7929496

DNA aberrations in the epithelial cell component of adamantinoma of long bones.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -260- Hazelbag HM, Fleuren GJ, Cornelisse CJ, Van den Broek LJCM, Taminiau AHM, Hogendoorn PCW. Am J Pathol 1995; 147: 1770-1779. Medline 7495301

Adamantinoma of long bones. A histopathological and immunohistochemical study of 23 cases. Jundt G, Remberger K, Roessner A, Schulz A, Bohndorf K. Path Res Pract 1995; 191: 112-120. Medline 7567680

Distribution of extracellular matrix components in adamantinoma of long bones suggests fibrous-to-epithelial transformation. Hazelbag HM, Van den Broek LJCM, Fleuren GJ, Taminiau AHM, Hogendoorn PCW. Hum Pathol 1997; 28: 183-188. Medline 9023400

Cytogenetic analysis of adamantinoma of long bones. Further indications for a common histogenesis with osteofibrous dysplasia. Hazelbag HM, Wessels JW, Mollevangers P, Van den Berg E, Molenaar WM, Hogendoorn PCW. Cancer Genet Cytogenet 1997; 97 : 5-11. Medline 9242211

Expression of growth factors and their receptors in adamantinoma of long bones and the implications for its histogenesis. Bovee JVMG, Van den Broek LJCM, De Boer WI, Hogendoorn PCW. J Pathol 1998; 184: 24-30. Medline 9582523

Osteofibrous dysplasia-like adamantinoma of bone: a report of five cases with immunohistochemical and ultrastructural studies. Kuruvilla G, Steiner GC. Hum Pathol 1998; 29: 809-814. Medline 9712421

Adamantinoma-like Ewing's sarcoma: genomic confirmation, phenotypic drift. Bridge JA, Fidler ME, Neff JR et al. Am J Surg Pathol 1999; 23: 159-165. Medline 9989842

Trisomies 8 and 20 characterize a subgroup of benign fibrous lesions arising in both soft tissue and bone. Bridge JA, Swarts SJ, Buresh C et al. Am J Pathol 1999; 154: 729-733. Medline 10079250

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Expression of cytokeratin 1, 5, 14, 19 and transforming growth factors- beta1, beta2, beta3 in osteofibrous dysplasia and adamantinoma: A possible association of transforming growth factor-beta with basal cell phenotype promotion. Maki M, Saitoh K, Kaneko Y, Fukayama M, Morohoshi T. Pathol Int 2000; 50: 801-807. Medline 11107052

Adamantinoma-like Ewing's sarcoma and Ewing's-like adamantinoma. The t(11;22), t(21;22) status. Hauben E, Van den Broek LJCM, Van Marck E, Hogendoorn PCW. J Pathol 2001; 195: 218-221. Medline 11592101

Adamantinome des os longs: revue anatomo-clinique et liens avec la dysplasie osteofibreuse. Hazelbag HM, Hogendoorn PCW. Ann Pathol 2001; 21: 499-511. Medline 11910937

Extra copies of chromosomes 7, 8, 12, 19, and 21 are recurrent in adamantinoma. Kanamori M, Antonescu CR, Scott M et al. J Mol Diagn 2001; 3: 16-21. Medline 11227067

Adamantinoma. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Hogendoorn PCW, Hashimoto H. Lyon: IARC Press, 2002: 332-334. REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Hans Marten Hazelbag, Pancras C.W. Hogendoorn 2003 Citation This paper should be referenced as such : Hazelbag HM, Hogendoorn PCW . Bone: Adamantinoma. Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/AdamantinID5154.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Neuroendocrine tumors: Phaeochromocytoma

Identity Note Usually, the term "phaeochromocytoma" designe secreting adrenal medulla tumor. An extraadrenal tumor is indicated by the term "catecholamine-secreting paraganglioma". Other Catecholamine-secreting paraganglioma names Functional paraganglioma Clinics and Pathology Note Neuroendocrine tumours arise from neuroectodermal chromaffin tissue, usually develop within the adrenal medulla but could develop in extraadrenal sympathetic ganglia in 10 % of cases. Phaechromocytomas secrete catecholamines (epinephrine, norepinephrine, dopamine) in the circulation and could induce severe lethal cardiovascular and cerebrovascular complications. They are located in the abdomen and in the pelvis (adrenal medulla, organ of Zuckerkandl, urinary bladder, paraganglia chromaffin cells in association with nerves and plexus). In rare cases, they could develop in the mediastinum (chest, pericardium, thorax) or in the neck (carotid body) and in the head (glomus jugulare and tympanicum). Usually, the paragangliomas located in the neck and in the head are non functional. Phenotype / cell stem Crest neural cells origin Etiology Phaeochromocytoma is an inherited form of cancer in 10% to 25% of cases. In familial cases, pheochromocytoma is a component of one of the four following autosomal dominant syndromic diseases, Multiple Endocrine Neoplasia type 2 (MEN2), Von-Hippel-Lindau disease (VHL), Hereditary paraganglioma syndrome (PGL) and Neurofibromatosis type 1 (NF1). In 75 to 90% cases, it is a sporadic or a non syndromic disease of an unknown etiology. Epidemiology The annual incidence is estimated at 1/10 000. Clinics The clinical manifestations are commonly paroxystics and result from catecholamine secretion: blood pressure changes (hypertension ± hypotension, orthostatic hypotension, hypertension induced by postural change or by the palpation of the mass), tachycardia, excessive sweating, pallor of face, headaches, etcŠ. The diagnosis is given by the elevation of the 24-hour urinary total metanephrine-

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -263- (metanephrine plus normetanephrine)-to-creatinine ratio and by the location of the tumor by imagery tests (computed axial tomography, magnetic resonnance imaging, scintigraphy with 131I-MIBG, somatostatin receptor scintigraphy). Treatment The treatment is the surgical removal of the tumor in a reference center. The patient must be prepared by a preoperative alpha blockade in order to prevent severe hypertensive crises and complications at the time of surgery. The treatment of recurrence or metastases is surgery to reduce tumor mass and/or alternative therapy as irradiation with large doses of 131I-MIBG or radiotherapy of bones metastases. Evolution Usually phaeochromocytomas are benign tumors but they could be malignant (lymph nodes, bone or visceral metastases) in 10% of cases with recurrence and distant metastases. Tumor recurrence may occur months or years following the initial surgery. Cytogenetics Cytogenetics Allelic losses at chromosome 1p, 3p, 17p, and 22q have been Morphological reported in sporadic and familial forms of phaeochromocytomas and at chromosome 11q in head and neck paragangliomas. Genes involved and Proteins Note 271 patients with an apparently sporadic phaeochromocytoma, and identified 66 patients with a germline mutations (24%) have been tested. Of these 66, 11 patients had mutations of SDHD (4%), 12 of SDHB (4.5%), 13 of RET (4.8%) and 30 of VHL (11.3%) genes. The genetic testing of all patients with phaeochromocytoma is important to identify genetic defects which are relatively frequents even in apparently sporadic tumours, to organize the clinical management of the patients with an inherited form of the disease and to propose a presymptomatic familial genetic testing. Gene SDHB Name Location 1p36.1-p35 Dna / Rna 8 exons, 1100 bp, 35.45 kb. Protein The subunit B protein or iron-sulfur protein (280 amino acids, 31.62 kDa), which binds three different iron-sulfur clusters, is directly involved in the catalytic activity of succinate dehydrogenase (mitochondrial complex II). Germinal Germline mutations cause hereditary paraganglioma, non-familial mutation paraganglioma, familial and sporadic pheochromocytomas. Different germline mutations have been reported. Mutations in SDHB have been also published in cases of sporadic and familial malignant pheochromocytomas. Some tumors display a second hit with the loss of 1p chromosome containing the wild type allele of SDHB gene. As in SDHD-inherited tumors, the inactivation of SDHB protein induces a

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -264- complete loss of succinate deshydrogenase activity in the tumoral tissues and an activation of hypoxic-angiogenic pathway.

Gene VHL Name Location 3p25-p26 Dna / Rna 3 exons, 4862 bp, 12,37 kb Protein The pVHL (213 amino acids, 24.15kDa) is a tumor suppressor protein which forms a multimeric complex with elongin B, elongin C and cullin 2. It is involved in several processes including cell cycle control, control of extracellular matrix, mRNA stability but its main function is the regulation of hypoxia-inducible gene expression and the negative regulation of angiogenesis via VEGF, HIF and EPAS. The VHL disease predispose to the development of various tumors. Pheochromocytoma occurs in the type 2 of the disease. Germinal Germline mutations of VHL gene have been identified in >500 kindreds. mutation For the Von Hippel-Lindau (VHL) type 2, the mutations are missense mutations with recurrent mutations at codon 98 (Y98H), 167 (R167Q) and188 (L188V).

Gene RET Name Location 10q12.2 Dna / Rna 21 exons, 53.3kb Protein The RET protein (1114 amino acids, 124.32 kDa) is a receptor tyrosine kinase which is expressed in derivatives of neural-crest cells. The first identified ligand is the glial-derived neurotropic factor (GDNF). The activating mutations of proto-oncogene RET, which constitutively activate the kinase receptor, induce three different subtypes of multiple endocrine neoplasia II (MEN2). Phaeochromocytoma occurs in MEN2A (in association with medullary thyroid carcinoma and hyperparathyroidism) and in MEN2B (in association with medullar thyroid carcinoma, marfanoid habitus, mucosal neuromas and ganglioneuromatosis of the gastrointestinal tract). In MEN2A, the mutations are principally located in the cystein-rich domain in affecting one important cystein residue (in exon 10 the Cys609, Cys610, Cys618 and Cys620) in particular the codon Cys634 in exon 11, which are significantly associated with phaeochromocytoma development, and induce a RET homodimerization. The MEN2B is caused by mutation in the tyrosine kinase domain and principally by the M918T mutation (95% of cases) which activates the kinase activity. The identification of a MEN2 carrier by genetic testing is an indication to propose a prophylactic thyroidectomy.

Gene SDHD Name

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -265- Location 11q23 Dna / Rna 4 exons, 1313 bp, 131.25 kb Protein The complex II (succinate-ubiquinone oxidoreductase) is a key component of the mitochondrial respiratory chain and the tricarboxylic acid cycle. It is involved in the oxidation of succinate (succinate + ubiquinone = fumarate + ubiquinol) and carries electrons from FADH to CoQ. It is composed of four nuclear-encoded subunits. The subunit D protein or small subunit (cybS) (159 amino acids, 17.43 kDa) is one of the two integral membrane proteins anchoring the complex to membrane. The inactivation of SDHD protein in tumors, resulting of a germline SDHD mutation and a 11q LOH at tumoral level, induces the complete loss of succinate deshydrogenase activity. Germinal Germline SDHD mutations are mainly associated with head and/or neck mutation paragangliomas but several SDHD mutations have been reported in non familial and familial pheochromocytoma. Different types of mutations are described: false-sense mutations, insertions and deletions leading to protein truncation and missense mutations.

Gene NF1 Name Location 17q11 Dna / Rna 57 exons, 8959 bp, 279.3 kb Protein The neurofibromin 1 (2839 amino acids, 319.4 kDa) is a GTPase activating protein. In Von Recklinghausen neurofibromatosis or neurofibromatosis type 1, the risk of phaeochromocytoma is very low (<1%). The diagnosis of NF1 is essentially clinical (café au lait spots, neurofibromas, Lisch nodules, Crowe's sign, glioma of optic nerve, bone anomalies, positive family history, Š). The genetic testing is difficult due to the large size of the gene and the absence of an hot-spot region of mutations. Germinal Nucleotide substitutions, deletions or insertions have been described. mutation

External links GeneCards SDHB, OMIM 162200 Orphanet Pheochromocytoma Bibliography The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubinstein A, Viskochil D. JAMA 1997, 278: 51-57 Medline 97350963

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Tumor recurence and hypertension persistence after successful pheochromocytoma operation. Plouin PF, Chatellier G, Fofol I, Corvol P. Hypertension 1997; 29: 1133-1139. Medline 97293784

The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependant proteolysis. Maxwell PH, Wiesner MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. Nature 1999; 399: 271-275. Medline 99279691

Sporadic and Familial pheochromocytomas are associated with loss of at least two discrete intervals on chromosome 1p. Benn DE, Dwight T, Richardson AL, Delbridge L, Bambach CP, Stowasser M, Gordon RD, Marsh DJ, Robinson BG. Cancer Research 2000; 60:7048-7051. Medline 21028106

Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Gimm O, Armanios M, Dziema H, Neumann HP, Eng C. Cancer Res. 2000; 60: 6822-6825. Medline 21028068

Germline SDHD mutation in familial phaeochromocytoma. Astuti D, Douglas F, Lennard TW, Aligianis IA, Woodward ER, Evans DG, Eng C, Latif F, Maher ER. Lancet 2001; 357(9263): 1181-1182. Medline 21223149

Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER. Am J Hum Genet 2001; 69(1): 49-54. Medline 21303033

Consensus. Guidelines for diagnosis and therapy of MEN type 1 and type 2. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri GR, Libroia A, Lips CJM, Lombardi G, Mannelli M, Pacini F, Ponder BAJ, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA, Marx SJ. J Clin Endocrinol Metab 2001; 86: 5658-5671.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -267- Medline 21601881

Different loss of chromosome 11q in familial and sporadic parasympathetic paragangliomas detected by comparative genomic hybridization. Dannenberg H, de Krijger RR, Zhao J, Speel EJM, Saremaslani P, Dinjens WNM, Mooi WJ, Roth J, Heitz PU, Komminoth P. Am J Pathol 2001; 158: 1937-1942. Medline 21288661

Genotype-phenotype correlation in von Hippel-Lindau syndrome. Friedrich CA. Hum Mol Genet. 2001; 10(7): 763-767. Review. Medline 21157263

The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X. Am J Hum Genet. 2001; 69(6): 1186-1197. Medline 21559911

Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study. Nguyen L, Niccoli-Sire P, Caron P, Bastie D, Maes B, Chabrier G, Chabre O, Rohmer V, Lecomte P, Henry JF, Conte-Devolx B. Eur J Endocrinol. 2001; 144(1): 37-44 Medline 21097214

Factors associated with preoperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center. Plouin PF, Duclos JM, Soppelsa F, Boublil G, Chatellier G. J Clin Endocrinol Metab 2001; 86: 1480-1486 Medline 21195482

Prevalence of SDHB, SDHC and SDHD germline mutations in clinic patients with head and neck paragangliomas. Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH, Myers EN, Ferrell RE, Rubinstein WS. J Med Genet 2002; 39: 178-183. Medline 21895997

Hereditary paranglioma targets diverse paranglia. Baysal BE J Med Genet. 2002; 39:617-622. Review. Medline 22194473

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Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma. Cascon A, Ruiz-Llorente S, Cebrian A, Telleria D, Rivero JC, Diez JJ, Lopez-Ibarra PJ, Jaunsolo MA, Benitez J, Robledo M. Eur J Human Genet. 2002; 10, 457-461. Medline 22105870

SDHB mutation analysis in familial and sporadic phaeochromocytoma identifies a novel mutation. Cascon A, Cebrian, Ruiz-Llorente S, Telleria D, Benitez J, Robledo M. J Med Genet 2002; 39: e64 Medline 22249215

Pheochromocytoma--death of an axiom. Dluhy RG. N Engl J Med. 2002 ;346(19): 1486-1488. Medline 21996362

Loss of heterozygosity on the short arm of chromosome 1 in pheochromocytoma and abdominal paraganglioma. Edstrom Elder E, Nord B, Carling T, Juhlin C, Backdahl M, Hoog A, Larsson C. World J Surg 2002; 26(8): 965-971. Medline 22180342

Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rotig A, Jeunemaitre X. J Clin Endocrinol Metab. 2002; 87(10): 4771-4774. Medline 22250972

New insights into the genetics of familial chromaffin cell tumors. Koch CA, Vortmeyer AO, Zhuang Z, Brouwers FM, Pacak K. Ann N Y Acad Sci 2002; 970: 11-28. Review Medline 22268999

Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome. Lui WO, Chen J, Glasker S, Bender BU, Madura C, Khoo SK, Kort E, Larsson C, Neumann HP, Teh BT. Oncogene. 2002; 21(7): 1117-1122. Medline 21839850

Germ-line mutations in nonsyndromic pheochromocytoma. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -269- J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Appel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C; The Freiburg-Warsaw-Columbus Pheochromocytoma Study Group. N Engl J Med 2002; 346(19): 1459-1466. Medline 21996357

How many pathways to pheochromocytoma? Neumann HP, Hoegerle S, Manz T, Brenner K, Iliopoulos O. Semin Nephrol. 2002; 22(2): 89-99. Review. Medline 21889259

Familial Malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. Young AL, Baysal BA, Deb A, Young WF. J Clin Endocrinol Metab 2002; 87: 4101-4105. Medline 22202382

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Anne-Paule Gimenez-Roqueplo 2003 Citation This paper should be referenced as such : Gimenez-Roqueplo AP . Neuroendocrine tumors: Phaeochromocytoma. Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/pheochromocytomaID5026.html

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Soft tissue tumors: an overview

Identity Note Soft tissue tumours represent a heterogeneous and complex group of mesenchymal lesions that may show a broad range of differentiation. Histologic classification is based upon morphologic demonstration of a specific line of differentiation but, despite the extraordinary contribution of ancillary diagnostic techniques such as electron microscopy and immunohistochemistry, classification of mesenchymal neoplasms is still the subject of continuous debate. The true incidence of soft tissue tumors is nearly impossible to determine, especially for benign tumors, because many of these tumors are not biopsied. Soft tissue sarcomas compared with carcinomas and other neoplasms, do constitute fewer than 1% of all cancers. Their morphological appearance is kaleidoscopic and extremely varied. Hence, classification is often difficult and the subject of continuous debate among pathologists.

For the purpose of uniformity the new World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone will be followed. Dermatofibrosarcoma protuberance and giant cell fibroblastoma, which are fibroblastic neoplasms included in the WHO volume on Skin Tumors, are also included in this review.

The vast majority of so-called smooth muscle tumors arising in the gastrointestinal tract are in fact gastrointestinal stromal tumors, and these lesions are included in the WHO Classification of Tumors Pathology and Genetics of Tumors of the Digestive System. Benign uterine leiomyomas are included in the WHO Classification of Tumors Pathology and Genetics of Tumors of the Breast and female genital organs.

Informations and (review) references are provided for well-characterized cytogenetic/molecular tumors investigated in more than a single case. Clinics and Pathology Disease ADIPOCYTIC TUMORS Cytogenetics Lipoma: More than half the cases studied show an abnormal karyotype, mostly balanced translocation, as single abnormality. Three distinct clustering of breakpoints have been distinguished: 1) the major group involving 12q13-15, with several possible partners, of which 3q27-28 is a preferential one; 2) a deletion/translocation of 13q11-q22;

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -271- 3) a rearrangement of 6p21-23. The target gene in 12q13-15 is a family member of the High Mobility Group (HMG) of protein, HMGA2 (a.k.a. HMGIC). In its preferential translocation region, 3q27-28, HMGA2 fuses its DNA binding domains to the protein-binding interfaces of the protein of a gene called LPP, which shows sequence similarity to the LIM protein family. Another member of the same HMG family, HMG1A (a.k.a. HMGIY) is the target in lipoma with 6p21-23 rearrangements. Lipoblastoma: The characteristic cytogenetic feature is rearrangement of 8q11-13. This rearrangement is associated with promoter swapping, in which the PLAG1 promoter element is replaced by those of the hyaluronic acid synthase 2 ( HAS2) or collagen ( COL1A2) genes. Angiolipoma: All cytogenetically investigated tumors but one have normal karyotypes. Chondroid lipoma: A seemingly balanced t(11;16)(q13;p12-13) has been reported in two cases Spindle cell lipoma/Pleomorphic lipoma: Similar cytogenetic aberrations have been described in both entities: loss of material from the region 16q13-qter with or without monosomy 13, or partial loss of 13q. Hibernoma: Involvement of 11q13 region has been described. However, FISH analysis demonstrated that these rearrangements are more complex than can be detected by conventional G-banding and affect the seemingly normal chromosome 11. Atypical lipomatous tumor/Well-differentiated liposarcoma: Supernumerary ring or/and giant marker chromosomes have been observed mostly as the sole chromosome aberration. Cells containing ring and/or giant markers varying in size or number can be observed in the same tumor sample. Telomeric associations are frequently seen. Molecular cytogenetic techniques indicate that both ring and giant marker chromosomes are composed of interspersed amplified sequences consistently originating from the 12q14-15 region. The most consistently amplified gene is MDM2, usually accompanied by amplification of neighbouring genes , such as SAS, CDK4 and HMGA2 (a.k.a. HMGIC). Additional chromosomal regions have been show to be coamplified with 12q14-15. Dedifferentiated liposarcoma: Cytogenetic anomalies similar to those seen in atypical lipomatous tumors/ well differentiated liposarcomas have been reported. Myxoid liposarcoma: The characteristic cytogenetic feature is t(12;16)(q13;p11), leading to the fusion of DDIT3 (a.k.a. CHOP) and FUS (a.k.a. TLS) genes. A rare variant translocation has been also described, t(12;22)(q13;q12), in which DDIT3 is fused with EWS.The absence of FUS/DDIT3 fusion in other morphologic mimics , such as myxoid well differentiated liposarcomas of the retroperitoneum and myxofibrosacoma, has been demonstrated. Pleomorphic liposarcoma: High chromosome number with complex structural rearrangements have been often described.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -272- Disease FIBROBLASTIC/MYOFIBROBLASTIC TUMORS Cytogenetics Nodular fasciitis: A rearrangement of 3q21 with a group D chromosome has been described in 2 of the 3 reported cases. Proliferative fasciitis and proliferative myositis: For each of these entities, trisomy 2 has been reported in a single case. Elastofibroma: A significant chromosomal instability has been reported. Aberrations of the short arm of chromosome 1 were particularly noted. Fibroma of the tendon sheath: A single case with t(2;11)(q31- 32;q12) has been reported. Desmoplastic fibroblastoma: Involvement of the same region of 11q12 has been observed in two cases. Mammary-type fibroblastoma: Partial monosomy 13q with or without partial monosomy 16q have been reported, similar to those described for spindle cell lipoma. Giant cell angiofibroma: One single case reported an abnormality of 6q13. Superficial fibromatoses: Near Ðdiploid karyotypes with simple numerical changes, particularly gain of chromosome 7 or 8, have been reported . Desmoid-type fibromatoses: Trisomies for chromosome 8 and/or 20 have been described in some cases. Rearrangement of 5q is found in desmoid tumors from patients with familial polyposis. APC inactivation has been described, as well as beta-catenin activating mutations. Extrapleural solitary fibrous tumor: No consistent abnormality has been detected. A possible involvement of 4q13 has been suggested. Hemangiopericytoma: Disparate chromosome aberrations have been described. The 12q13-q15 and 19q13 have been the most frequent breakpoints described. Inflammatory myofibroblastic tumor: Involvement of 2p23 occurs mainly or exclusively in children and young adults. Activation of the ALK receptor tyrosine kinase is accomplished by chromosomal fusion with TPM4(19p13.1), TPM3(1q22.23) and CLTCL2(17q23) and is restricted to the myofibroblastic component of the tumors. The aberrations of ALK gene have been originally characterized as a component of the anaplastic large cell lymphoma NPM-ALK fusion oncoprotein. Infantile fibrosarcoma: A specific t(12;15)(p13;q26) is the hallmark of this tumor. Since the regions exchanged between chromosomes 12 and 15 are similar in size and banding characteristics, this translocation was overlooked in early reports , in which only numerical changes i.e. trisomies 11, 8, 17 and 20 were described. This translocation fuses the ETV6(a.k.a. TEL) gene at 12p13 with the neurotrophin-3 receptor gene NTRK3(a.k.a. TRKS) at 15q25. Notably, cellular congenital mesoblastic nephroma correlates with the presence of the same t(12;15) and with trisomy 11, but these findings are not seen in the classical congenital mesoblastic nephroma.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -273- Adult fibrosarcoma: No consistent abnormality has been detected among the complex karyotypes published to date. Myxofibrosarcoma: Highly complex karyotypes with extensive intratumoral heterogeneity have been reported. No consistent aberration has emerged. Low grade fibromyxoid sarcoma: No consistent abnormality has been detected. Sclerosing epitheliod fibrosarcoma: No consistent abnormality has been detected among the 3 tumors so far reported. Dermatofibrosarcoma protuberans/Giant cell fibroblastoma: The t(17;22)(q22;q13) and, more often a supernumerary ring chromosome derived from this translocation , are the characteristic chromosome aberrations in these entities . In some rings additional segments from other chromosomes could been identified. Both rings and translocations contain a fusion of two genes COL1A1 (17q21-22) and PDGFB (22q13).

Disease SO-CALLED FIBROHISTIOCYTIC TUMORS Cytogenetics Giant cell tumor of tendon sheath: The region most frequently involved in structural rearrangements is 1p11-13. Chromosome 2q35- 36 region is the most common translocation partner described. Other chromosome aberrations observed include involvement of 16q24 and trisomies 5 and/or 7. A breakpoint clustering to the sequences corresponding to YAC probes 914F6 and 88F12, located in 1p3.2, has been identified. Diffuse-type giant cell tumors: The structural and numerical abnormalities described are similar to those observed in (localized form) giant cell tumor of the tendon sheath, however trisomies for chromosomes 5 and 7 are more frequently encountered in the diffuse form of the tumor. Plexiform fibrohistiocytic tumor: No consistent abnormality has been detected among the 2 tumors so far reported. Pleomorphic malignant fibrous histiocytoma: In general the karyotypes tend to be the triploi-tetraploid range, with complex chromosome aberrations, numerous marker chromosomes and with extensive intratumoral heterogenity. No common chromosome aberrations emerge, but telomeric associations, ring chromosomes and dicentric chromosomes are frequently encountered.

Disease SMOOTH MUSCLE TUMORS Cytogenetics Angioleiomyoma: No consistent abnormality has been reported from the 4 tumors investigated to date. Leiomyosarcoma: Most karyotypes are complex and no consistent aberrations have been reported

Disease PERICYTIC (PERIVASCULAR) TUMORS Cytogenetics No cytogenetic investigations have been reported in this category of soft tissue tumors.

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Disease SKELETAL MUSCLE TUMORS Cytogenetics Embryonal rhabdomyosarcoma: Complex karyotype are generally reported, including extra copies of chromosomes 2, 8 and 13, and rearrangements of chromosome 1. However, loss of heterozygosity of 11p15 region is found in most of these tumors. Imprited tumor supressor genes i.e. IGF2, H19and CDKN1Chave been suggested as the the mechanism of tumorigenesis in these tumors. Alveolar rhabdomyosarcoma.: A specific t(2;13)(q35;q14) characterizes this type of rhabdomyosarcoma. The genes involved are the PAX3 gene on 2q35 and the FKHR gene on 13q14. A variant translocation has been described, t(1;13)(p36;q14), which fuses PAX7gene on 1p36 with FKHR. Tumors with PAX7-FKHR fusion transcript show a predeliction for younger patients, appear in the extremities and have a better prognosis Pleomorphic rhabdomyosarcoma: Highly complex karyotypes have been reported.

Disease VASCULAR TUMORS Cytogenetics Kaposi sarcoma: No consistent abnormality has been detected neither cell lines or primary tumors. Epithelioid hemangioendothelioma: An identical t(1;3)(p36;.3q25) has been reported in 2 cases. Angiosarcoma of the soft tissue: All reported tumors, but one, have complex cytogenetic aberrations without consistent recurring chromosome aberration. However there are some recurrent aberrations among angiosarcomas arising in the same location.

Disease CHONDRO-OSSEOUS TUMORS Cytogenetics Soft tissue chondroma: No consistent abnormality has been detected among the 4 tumors studied to date. Extraskeletal osteosarcoma: No consistent abnormality has been detected among the 3 tumors studied to date.

Disease TUMORS OF UNCERTAIN DIFFERENTIATION Cytogenetics Intramuscular myxoma: One single case reported a hyperdiploid clone with trisomy 18. Juxta-articular myxoma: One single case reported two unrelated abnormal clones. Deep "aggressive" angiomyxoma: Abnormalities of chromosome 12 have been reported. The most frequently rearranged chromosome region is 12q13-15 and HMGA2 is the target gene. Angiomatoid fibrous histicytoma: One case exhibited a complex translocation involving chromosomes 2,17,12, and 16. Further molecular investigation revealed that the FUS (also known as TLS) gene, mapping to chromosome band 16p11, was fused with the ATF1gene, located in band 12q13. The translocation thus generates a

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -275- chimeric FUS/ATF1 protein, similar to the EWS/ATF1 chimeric protein seen in clear cell sarcomas with t(12;22) (q13;q12). Identical fusion of FUS and ATF1 genes were reported in a second case. Ossifying fibromyxoid tumor: One single case has been reported. Mixed tumor/Myoepithelioma/Parachordoma: No consistent abnormality has been detected among the 3 tumors studied to date. Synovial sarcoma: A specific t(X;18)((p11.2;q11.2) characterizes both monophasic and biphasic morphologic variants. The vast majority of primary tumors shows a near-diploid karyotype, while the recurring and metastasis lesions carry additional chromosome aberrations. Involvement of a third (or more) chromosome has been reported. The t(X;18) results in two gene fusions in which the SYT gene at 18q11.2 joins either of two closely related genes at Xp11.2, designated SSX1or SSX2. The monophasic variant exhibits SYT-SSX1or SYT-SSX2 transcripts and the majority of the biphasic one SSX1. The formation of the respective fusions is generally mutually exclusive and remains constant during the course of the disease. Moreover the SYT-SSX2 fusion is considered a strongly positive prognostic factor for overall survival because it is associated with a lower prevalence of metastatic disease at diagnosis. Epithelioid sarcoma: No consistent abnormalities have been detected. A possible role of 8q has been suggested. Alveolar soft part sarcoma: A specific chromosome aberration, der (17)t(X;17)(p11;q25), is the hallmark of this sarcoma. This translocation fuses the TFE3 transcription factor gene at Xp11.2 to a novel gene at 17q25, designated as ASPL(a.k.a ASP-SCR1 or RCC17). Of interest, the balanced t(X;17)(p11.2;q25) has been also described in renal tumors of young people. An identical ASPL-TFE33 fusion transcript, seen in alveolar soft part sarcoma, has been detected ,as has the reciprocal fusion transcript TFE3-ASPL. Ewing sarcoma/Primitive neuroectodermal tumor: The t(11;22)(q24;q12) was the first specific change to be defined in sarcoma. Cytogenetics variants usually involving a third chromosome have been described. Secondary changes i.e. +8, +12 and der(16)t(1;16) were also frequently reported. The t(11;22)(q24;q12) results of the fusion of the Ewing sarcoma (EWS) gene at 22q12 and the FLI1 gene at 11q24. However variant translocation have been reported , where the EWS gene fuses with different partner genes such as the ERG gene at 21q22, the ETV1 at 7p22, E1AF at 17q12, FEV at 2q23 and ZSG at 22q12. A variability in molecular transcripts has been reported and a few clinical correlation already emerged. Patients wit EWS-FLI1 transcripts other that type 1, have a poor prognosis regardless of stage , tumor location or age. Clear cell sarcoma of the soft tissue: The t(12;22)(q13;q12) emerged as a characteristic cytogenetic change in the type of sarcoma. No variant translocations have been reported to date. The translocation results in fusion of the EWS (22q12) and ATF1 (12q13) genes. Extraskeletal myxoid chrondrosarcoma: A specific chromosomal abnormality, t(9;22)(q22;q12) characterizes this entity, though variant translocations have been also described. Variant translocations have

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -276- been also reported: t (9;17)(q22;q11) and t(9;15)(q22;q21). All three translocations result in fusion of the NR4 A3 (a.k.a. CHN, TEC) gene at 9q22 with the EWS gene at 22q12, or with RBP56 gene at 17q11 or with TCF12 gene at 15q21. Desmoplastic small round cell tumor: A specific chromosomal abnormality, t(11;22)(p13;q12) characterizes this entity, though variant translocations have been also described. The t(11;22) results in the fusions of two chromosomal region previously implicated in other malignant tumors: the Wilms tumor gene (WT1) localized to 11p13 and the Ewing sarcoma (EWS) gene localized to 22q12. Extrarenal rhabdoid tumor: Abnormalities of 22q11.2, as translocations and deletions, have been described in these distinct tumors arising in any part of the human body. Mutations and homozygous deletions of the SMAR-CB1 (a.k.a. hSNF5 or INI1) gene have been detected. PEComas (perivascular epithelioid cell tumors): One single case has been reported. Bibliography Trisomy 2 in proliferative fasciitis. Dembinski A, Bridge JA, Neff JR, Berger C, Sandberg AA Cancer Genet Cyogenet 1992; 60:27-30. Medline 1591703

Trisomy 2 found in proliferative myositis cultured cells. Ohjimi Y, Iwasaki H, Ishiguro M, Isayama Y, Kaneko Y. Cancer Genet Cytogenet 1994; 76: 157. Medline 7923069

Deletion 5q in desmoid tumor and fluorescence in situ hybridization for chromosome 8 and/or 20 copy number. Bridge JA, Meloni AM, Neff JR, Deboer J, Pickering D, Dalence C, Jeffrey B, Sandberg AA. Cancer Genet Cytogenet 1996; 92: 150-151. Medline 8976374

Cytogenetic analysis of subcutaneous angiolipoma: further evidence supporting its difference from ordinary pure lipomas: a report of the CHAMP Study Group. Sciot R, Akerman M, Dal Cin P, De Wever I, Fletcher CD, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Tallini G, Van den Berghe H, Vanni R, Willen H. Am J Surg Pathol 1997;21: 441-444. Medline 9330991

Translocation 2;11 in a fibroma of tendon sheath. Dal Cin P, Sciot R, De Smet L, Van den Berghe H. Histopathology 1998; 32: 433-435. Medline 9639118

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Mutations of adenomatous polyposis coli (APC) gene are uncommon in sporadic desmoid tumours. Giarola M, Wells D, Mondini P, Pilotti S, Sala P, Azzarelli A, Bertario L, Pierotti MA, Delhanty JD, Radice P. Br J Cancer 1998; 78: 582-587. Medline 9744495

HMGIY is the target of 6p21.3 rearrangements in various benign mesenchymal tumors. Kazmierczak B, Dal Cin P, Wanschura S, Borrmann L, Fusco A, Van den Berghe H, Bullerdiek J. Genes Chromosomes Cancer 1998; 23: 279-285. Medline 9824199

Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O. Nature 1998; 394: 203-206. Medline 9671307

Involvement of 3q21 in nodular fasciitis Weibolt VM, Buresh CJ, Roberts CA, Suijkerbuijk RF, Pickering DL, Neff JR, Bridge JA. Cancer Genet Cytogenet 1998; 15(106): 177-179. Medline 9797787

Correlation between clinicopathological features and karyotype in spindle cell sarcomas. A report of 130 cases from the CHAMP study group. Fletcher CD, Dal Cin P, de Wever I, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, van den Berghe H, Vanni R, Willen H. Am J Pathol 1999;154: 1841-1847. Medline 10362810

Hibernomas are characterized by homozygous deletions in the multiple endocrine neoplasia type I region. Metaphase fluorescence in situ hybridization reveals complex rearrangements not detected by conventional cytogenetics. Gisselsson D, Hoglund M, Mertens F, Dal Cin P, Mandahl N. Am J Pathol 1999; 155: 61-66. Medline 10393837 hSNF5/INI1 inactivation is mainly associated with homozygous deletions and mitotic recombinations in rhabdoid tumors. Rousseau-Merck MF, Versteege I, Legrand I, Couturier J, Mairal A, Delattre O, Aurias A. Cancer Res 1999;59: 3152-3156.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -278- Medline 10397258

Analysis of 35 cases of localized and diffuse tenosynovial giant cell tumor: a report from the Chromosomes and Morphology (CHAMP) study group. Sciot R, Rosai J, Dal Cin P, De Wever I, Fletcher CD, Mandahl N, Mertens F, Mitelman F, Rydholm A, Tallini G, van den Berghe H, Vanni R, Willen H. Modern Pathol 1999;12: 576-579. Medline 10392632

Collagenous fibroma (desmoplastic fibroblastoma): genetic link with fibroma of tendon sheath? Sciot R, Samson I, van den Berghe H, Van Damme B, Dal Cin P. Mod Pathol 1999;12: 565-568. Medline 10392630

Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor). Tejpar S, Nollet F, Li C, Wunder JS, Michils G, dal Cin P, Van Cutsem E, Bapat B, van Roy F, Cassiman JJ, Alman BA. Oncogene 1999 11;18: 6615-6620. Medline 10597266

Specificity of TLS-CHOP rearrangement for classic myxoid/round cell liposarcoma: absence in predominantly myxoid well-differentiated liposarcomas. Antonescu CR, Elahi A, Humphrey M, Lui MY, Healey JH, Brennan MF, Woodruff JM, Jhanwar SC, Ladanyi M. J Mol Diagn 2000; 2: 132-138. Medline 11229517

Common chromosome aberrations in the proximal type of epithelioid sarcoma. Debiec-Rychter M, Sciot R, Hagemeijer A. Cancer Genet Cytogenet 2000; 123: 133-136. Review. Medline 11150604

Coordinated expression and amplification of the MDM2, CDK4, and HMGI-C genes in atypical lipomatous tumours. Dei Tos AP, Doglioni C, Piccinin S, Sciot R, Furlanetto A, Boiocchi M, Dal Cin P, Maestro R, Fletcher CD, Tallini G. J Pathol 2000; 190: 531-536. Medline 10727978

Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology De Wever I, Dal Cin P, Fletcher CD, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, Van Den Berghe H, Vanni R, Willen H.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -279- Mod Pathol 2000; 13: 1080-1085. Medline 11048801

Sclerosing epithelioid fibrosarcoma: a cytogenetic, immunohistochemical, and ultrastructural study of an unusual histological variant. Donner LR, Clawson K, Dobin SM. Cancer Genet Cytogenet 2000; 119: 127-31. Review. Medline 10867148

Cytogenetic findings in a case of epithelioid sarcoma and a review of the literature. Feely MG, Fidler ME, Nelson M, Neff JR, Bridge JA. Cancer Genet Cytogenet 2000; 119: 155-157. Review. Medline 10867152

PLAG1 fusion oncogenes in lipoblastoma. Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, Xiao S, Fletcher Cancer Res 2000;60: 4869-4872. Medline 10987300

Aberrant ALK tyrosine kinase signaling. Different cellular lineages, common oncogenic mechanisms. Ladanyi M. Am J Pathol 2000; 157: 341-345. Medline 10934137

Comparative cytogenetic study of spindle cell and pleomorphic leiomyosarcomas of soft tissues: a report from the CHAMP Study Group. Mandahl N, Fletcher CD, Dal Cin P, De Wever I, Mertens F, Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, Van Den Berghe H, Vanni R, Willen H. Cancer Genet Cytogenet 2000;116: 66-73. Medline 10616536

Myofibroblastoma of the breast: genetic link with spindle cell lipoma. Pauwels P, Sciot R, Croiset F, Rutten H, Van den Berghe H, Dal Cin P. J Pathol 2000;191: 282-285. Medline 10878550

Updates on cytogenetics and molecular genetics of bone and soft tissue tumors: Ewing sarcoma and peripheral primitive neuroectodermal tumors. Sandberg AA, Bridge JA. Cancer Genet Cytogenet 2000;123: 1-26. Review. Medline 11120329

Fusion of the NH2-terminal domain of the basic helix-loop-helix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -280- t(9;15)(q22;q21). Sjogren H, Wedell B, Meis-Kindblom JM, Kindblom LG, Stenman G, Kindblom JM. Cancer Res 2000; 15; 60: 6832-5. Medline 11156374

A giant cell angiofibroma involving 6q. Sonobe H, Iwata J, Komatsu T, Fukushima A, Hayashi N, Moriki T, Shimizu K, Ohtsuki Y. Cancer Genet Cytogenet 2000; 116(1): 47-49. Medline 10616532

HMGI-C and HMGI(Y) immunoreactivity correlates with cytogenetic abnormalities in lipomas, pulmonary chondroid hamartomas, endometrial polyps, and uterine leiomyomas and is compatible with rearrangement of the HMGI-C and HMGI(Y) genes. Tallini G, Vanni R, Manfioletti G, Kazmierczak B, Faa G, Pauwels P, Bullerdiek J, Giancotti V, Van Den Berghe H, Dal Cin P. Lab Invest 2000;80:359-369. Medline 10744071

Unique cytologic and chromosome aberrations in chondroid lipoma. Thomson TA, Bainbridge TC, Horsamn D. Am J Surg Pathol 2000; 24: 1035. Medline 10895830

Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11. Waters BL, Panagopoulos I, Allen EF. Cancer Genet Cytogenet 2000;121:109-116. Medline 11063792

Is 4q13 a recurring breakpoint in solitary fibrous tumors? Debiec-Rychter M, de Wever I, Hagemeijer A, Sciot R. Cancer Genet Cytogenet 2001; 131 :69-73. Medline 11734322

Cytogenetic instability, predominantly involving chromosome 1, is characteristic of elastofibroma. McComb EN, Feely MG, Neff JR, Johansson SL, Nelson M, Bridge JA. Cancer Genet Cytogenet 2001; 126: 68-72. Medline 11343783

Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Mendlick MR, Nelson M, Pickering D, Johansson SL, Seemayer TA, Neff JR, Vergara

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -281- G, Rosenthal H, Bridge JA. Am J Surg Pathol 2001; 25:684-687. Medline 11342784

Chromosomal translocation t(8;12) induces aberrant HMGIC expression in aggressive angiomyxoma of the vulva. Nucci MR, Weremowicz S, Neskey DM, Sornberger K, Tallini G, Morton CC, Quade BJ. Genes Chromosomes Cancer 2001; 32:172-176. Medline 11550285

Pathologic classification of rhabdomyosarcomas and correlations with molecular studies. Parham DM. Mod Pathol 2001;14: 506-514. Review. Medline 11353062

The genetics of lipomatous tumors Rubin BP, Dal Cin P Semin Diagn Pathol 2001;18: 286-293. Review. Medline 11757869

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: clear cell sarcoma (malignant melanoma of soft parts). Sandberg AA, Bridge JA. Cancer Genet Cytogenet 2001;130:1-7. Review. Medline 11672766

World Health Organization: Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Fletcher CDM, Unni KK, Mertens F. IARC Press: Lyon 2002.

Molecular cytogenetic mapping of recurrent chromosomal breakpoints in tenosynovial giant cell tumors. Nilsson M, Hoglund M, Panagopoulos I, Sciot R, Dal Cin P, Debiec-Rychter M, Mertens F, Mandahl N. Virchows Arch 2002; 44: 475-480. Medline 12447678

Fusion of the FUS and ATF1 genes in a large, deep-seated angiomatoid fibrous histiocytoma. Raddaoui E, Donner LR, Panagopoulos I. Diagn Mol Pathol 2002;11:157-162. Medline 12218455

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -282- Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: congenital (infantile) fibrosarcoma and mesoblastic nephroma. Sandberg AA, Bridge JA. Cancer Genet Cytogenet 2002;132: 1-13. Review. Medline 11801301

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Synovial Sandberg AA, Bridge JA. Cancer Genet Cytogenet 2002;133: 1-23. Review. Medline 11890984

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Desmoplastic small round-cell tumors. Sandberg AA, Bridge JA. Cancer Genet Cytogenet 2002;138: 1-10. Review. Medline 12419577

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: dermatofibrosarcoma protuberans and giant cell fibroblastoma. Sandberg AA, Bridge JA. Cancer Genet Cytogenet 2003;140: 1-12. Review. Medline 12550751

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Paola Dal Cin 2003 Citation This paper should be referenced as such : Dal Cin P . Soft tissue tumors: an overview. Atlas Genet Cytogenet Oncol Haematol. January 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/softissuTumID5042.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -283- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Heterochromatin , from Chromosome to Protein Marie-Geneviève Mattei and Judith Luciani

INSERM U 491, Faculté de Médecine, Bd Jean Moulin, 13385 Marseille, France (Paper co-edited with E.C.A. Newsletter) January 2003

I THE CONCEPT OF HETEROCHROMATIN Definition of Chromatin In prokaryotes such as Escherichia coli there is no detectable heterochromatin, for the simple reason that there is no chromatin. The hereditary message is carried by a circular molecule of naked DNA, and there is no separate nuclear compartment. In eukaryotes, however, the DNA is packaged in the form of a nucleoprotein complex called "chromatin". The hereditary message is, therefore, carried by the chromatin. It is located in a nucleus and is organised in several separate entities, the chromosomes. The Concept of Heterochromatin The concept of heterochromatin, as described by Emil HEITZ in 1928, was exclusively based on histological observations. He defined heterochromatin (HC) as being the chromosomal segments which appear extremely condensed and dark in colour in the interphase nucleus. The rest of the nucleus is occupied by euchromatin, or true chromatin, which appears diffuse and relatively light in colour. Heitz's observations highlighted the fact that, in the interphase nucleus, chromatin does not have a homogeneous appearance. Electron microscopy and X-ray diffraction have since confirmed the heterogeneous structure of chromatin: it consists of a tangle of fibres, the diameter of which not only vary during the cell cycle, but also depend on the region of the chromosome observed. Euchromatin, in its active form, consists of a fibre with a diameter not exceeding 10-11nm. Its diameter corresponds to that of a nucleosome, which contains a 146 base pair double strand DNA segment, wound around 4 homodimers of the histones H2A, H2B, H3, and H4 . The inactive euchromatin is enriched in linker histone H1. Histone H1 binds two consecutive nucleosomes, which causes the 10-11nm fibre to wind itself into a solenoid with a 30nm diameter. The 30nm fibre is further organised through interactions with non-histone proteins which fold the chromatin fibre in loops around an imaginary axis. These proteins include topoisomerase II, which is located, in particular, at the base of the loops, the scaffold protein 2 and lamins, in addition to other proteins. At this stage, the diameter of the chromatin fibre attains approximately 200nm. As regards the heterochromatin, as defined above, its constituent fibre is more condensed and often appears to be composed of aggregates. It involves numerous additional proteins, including the HP1 proteins (Heterochromatin Protein 1).

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II TWO TYPES OF HETEROCHROMATIN There are two types of heterochromatin, constitutive HC and facultative HC, which differ slightly, depending on the DNA that they contain. The richness in satellite DNA determines the permanent or reversible nature of the heterochromatin, its polymorphism and its staining properties (Table I).

Table I: Properties which allow to differentiate constitutive from facultative heterochromatin.

1) Richness in satellite DNA

• Constitutive HC contains a particular type of DNA called satellite DNA, which consists of large numbers of short tandemly repeated sequences. There are various types of satellite DNA which can be separated by gradient density centrifugation. The best-known type, which is called alpha-satellite DNA, is rich in A-T and is located in the centromeric region of the chromosomes. DNA satellite I, which is also A-T rich, is located more specifically at the centromeres of chromosomes 3 and 4, the short arms of the acrocentrics, and the long arm of the Y chromosome. The DNA satellites II and III are both A-T rich, but they are also G-C rich. DNA satellite II is primarily located at the secondary constrictions of chromosomes 1 and 16. Satellite III is mostly present in the secondary constriction of chromosome 9, the short arms of the acrocentrics and the Y chromosome. The satellite DNA sequences have the distinctive feature of being able to fold on themselves and may have an important role in the formation of the highly compact structure of the constitutive HC.

• Facultative HC is not enriched in satellite DNA. It is characterised by the presence of G-bands, which are rich in LINE-type repeated sequences. These sequences, dispersed throughout the genome, could promote the propagation of a condensed chromatin structure.

2) Stability:

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -285- • Constitutive HC is stable and conserves its heterochromatic properties during all stages of development and in all tissues. This "heterochromatic" state is linked to the satellite DNA it contains, and thus to the sequence of that DNA, which is clearly not reversible.

• Facultative HC is reversible, that is to say, it can change from the heterochromatic state to a euchromatic state, depending on the stage of development or the cell type examined. In this case, the reversibility of the heterochromatic state clearly demonstrates that the DNA sequence is not involved. In females, one of the X chromosomes is inactive and has a heterochromatic state (Barr body) in the somatic cells. Before entering meiosis, it is reactivated and both X chromosomes form a normal bivalent, undistinguishable from the autosomal bivalents. The inactive X provides a classic example of facultative HC. Another example of facultative HC is observed at the pachytene stage of male meiosis. At this stage, the X and Y chromosomes, joined by their telomeres, condense to form the inactive sex vesicle (SV). The heterochromatic state of the sex chromosomes at the pachytene stage of meiosis is transitory, and the SV can therefore be considered as being facultative HC.

3) Polymorphism

• Constitutive HC is highly polymorphic. This polymorphism can affect not only the size but also the localisation of the heterochromatin, and apparently has no phenotypic effect. Such variations are clearly observed on the secondary constriction of chromosome 9. The frequent polymorphisms that characterise constitutive HC are due to the instability of the satellite DNA.

• The facultative HC is not particularly rich in satellite DNA, and is therefore not polymorphic.

4) C-band Staining :

• Constitutive HC is strongly stained by the C-band technique. This staining could be the result of the very rapid renaturation of the satellite DNA following denaturation.

• Facultative HC is never stained by the C-band technique.

III PROPERTIES OF HETEROCHROMATIN Despite the differences described above, constitutive HC and facultative HC have very similar properties.

1) Heterochromatin is condensed

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -286- This is in fact what defines heterochromatin, and it is applicable to both constitutive HC and facultative HC. This high condensation renders it strongly chromophilic, and the intensity of HC staining is directly proportional to its degree of condensation. The strongly condensed nature of heterochromatin has another consequence, in that it renders it inaccessible to DNAse 1 and to other restriction enzymes in general.

2) Heterochromatin DNA is late replicating

The incorporation of various nucleotide analogues shows that the DNA from both constitutive and facultative HC, is late replicating. The DNA of the inactive X is very late replicating, as it replicates at the end of the late S phase. The incorporation of 5-Bromodeoxyuridine four hours before harvesting allows this to be clearly seen. As regards the heterochromatic centromere regions, their replication precedes that of the inactive X and takes place at the beginning of the late S phase. The centromeric DNA must, therefore, replicate sufficiently early to allow the formation, with the centromeric proteins, of a nuclear-protein complex that will be functional during mitosis.

• The late replication of the HC results, on the one hand, from its high degree of condensation, which prevents the replicating machinery from easily accessing the DNA, and, on the other hand, from its location in a peripheral nuclear domain that is poor in active elements. • The late replication of HC also leads to a less efficient repair of its DNA, in the event of polymerase errors.

3) Heterochromatin DNA is methylated

The DNA of constitutive HC is highly methylated, with the methylation occurring exclusively on the cytosines. An anti-5-methyl cytosine antibody therefore strongly labels all the regions of constitutive HC, thus showing both its richness in cytosines and their methylation. As regards facultative HC, the methylation of the DNA is more discrete, and cannot be detected using an antibody directed against methylated cytosines. Nevertheless, restriction enzymes that are sensitive to methylation can be used to reveal strong methylation of the CpG islands, which are specifically located in the control regions of the genes.

4) In heterochromatin, histones are hypo-acetylated:

Histones may undergo post-translational modifications of their N-terminal ends which may affect the genetic activity of the chromatin. It has long been known that the hypo-acetylation of histone N-terminal tails is a modification that is associated with an inactive chromatin. In contrast, however, hyper-acetylated histones characterise the active chromatin. It is principally the lysines ("K" in single-letter code language) of the histones that are acetylated.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -287- Acetylation/de-acetylation of histones is a mechanism that is absolutely essential for the control of gene expression. Numerous transcription factors have been shown to have, either an activity Histone Acétyl Transférase (HAT) in the case of co-activators, or Histone De-ACétylases (HDAC) in the case of co-repressors.

5) Histones from heterochromatin are methylated on lysine 9:

This modification of the N-terminal tail of histones has only very recently been discovered and found to be involved in the process of heterochromatinisation of the genome. It characterises both constitutive HC and facultative HC. Methylation of the H3 histone occurs on a very specific residue, lysine 9, hence its name, H3-K9. The H3-K9 lysine may be mono-methylated, di-methylated or tri- methylated, and a high degree of methylation promotes the binding of the HP1 (Heterochromatin Protein 1) proteins.

6) Heterochromatin is transcriptionally inactive:

Incorporating tritiated uridine into a cell culture does not result in any labelling of the heterochromatin. Human constitutive HC does not contain any genes, which explains why transcription does not take place at these sites. In Drosophila, on the other hand, certain genes, such as the rolled and light genes, are usually located in and expressed from the constitutive HC. The facultative HC is relatively poor in genes, and its genes are not usually transcribed in a heterochromatic context.

7) Heterochromatin does not participate in genetic recombination:

It is generally accepted that constitutive HC does not participate in genetic recombination. The reason for this is that there is no preliminary pairing of the homologous heterochromatic regions, even though some aggregation of these regions is often observed. In any case, the polymorphism that characterises the heterochromatic regions would render such pairing difficult, if not impossible. Moreover, this is the reason why the pericentric inversion of the secondary constriction of chromosome 9 has no effect in terms of chromosome mechanics and can be considered as a normal variant. Not only does the constitutive HC not participate in recombination, it also acts to repress recombination in adjacent euchromatic regions. As regards the facultative HC, it does not participate in meiotic recombination when it is in its inactive form.

8) Heterochromatin has a gregarious instinct:

The study of various organisms has shown that constitutive HC has a genuine tendency to aggregate during interphase.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -288- Thus, in the interphase nuclei of the salivar glands of Drosophila larvae, the centromeres of polytene chromosomes, which are rich in heterochromatin, aggregate to form the chromocentres. In the mouse, the number of heterochromatic blocks that can be observed in interphase nuclei is always lower than the number of heterochromatic regions visualised on the metaphase chromosomes. The relationship between the size and the number of HC blocks in interphase suggests a coalescence of the heterochromatic regions. In the human, the short arms of the acrocentric chromosomes, which are mainly formed from heterochromatin, carry the nucleolar organiser regions. They are frequently associated in the interphase nucleus, and this does not appear to result solely from their common function. Indeed, numerous other chromosomes are involved in this association, and the participation of each of them is all the more marked because it carries a large HC block, as is the case for chromosomes 1, 9 or 16. This tendency of the heterochromatin to aggregate appears to be strongly linked to the presence of satellite DNA sequences, but this is a property which may not be exclusive and may involve other additional sequences.

IV FACTEURS INVOLVED in HETEROCHROMATINISATION There are probably various diverse ways of organising a genomic region into heterochromatin. Certain observations have, however, led to the identification of various elements that have an important role in the formation of heterochromatin, be it constitutive or facultative.

1) Large arrays of tandemly repeated sequences.

The fact that in the human genome, as well as in the genome of other organisms, the localisation of the satellite DNA visualised by FISH corresponds exactly to that of the constitutive heterochromatin stained by DAPI, highlights the potential role of satellite DNA in the formation of this type of heterochromatin. Indeed, this type of DNA sequence has the distinctive feature of bending and folding upon itself, and this may be an important factor in determining the extremely compact structure of the constitutive DNA. However, this does not only concern satellite DNA. In plants, Drosophila, and also in the mouse, certain multicopy transgenes are barely expressed, or are not expressed at all, even when they are not subject to centromere repression. These different observations suggest that the tandem repetition of a DNA sequence in a large number of copies is sufficient on its own to direct the formation of heterochromatin. The presence of repetitive DNA, such as satellite DNA, appears to simply allow the chromatin to be compacted to a greater extent, as is the case for constitutive heterochromatin. The mechanism would appear to be as follows: the large arrays of tandemly repeated DNA sequences appear to be able to pair, thus forming characteristic structures. These structures would then appear to be recognised by specific proteins, such as the HP1 proteins, which in turn direct the formation of a higher-order chromatin.

2) Methylation of DNA

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -289- Although the presence of tandemly repeated sequences is important, it is not the only factor, as large repetitions of transgenes do not all lead to a transcriptional inactivation of the transgene. Most often, the silencing induced by the tandem repeats appears to be linked to the presence of prokaryotic DNA sequences that are rich in CpG and, therefore, likely to be methylated (for example, the lacZ gene). The base composition of the tandem repeat and, in particular, its ability to be methylated could therefore play an important role in the formation of heterochromatin. Interestingly, it has recently been shown that there is a direct relationship between the methylation of DNA and the de-acetylation of histones, both of which characterise heterochromatic structures. The methyl binding protein MeCP2, which normally binds to DNA containing methylated cytosines, has thus been shown to be able to recruit histone de-acetylases (Figure 1). Methylation of the DNA could therefore induce a de-acetylation of histones and thus promote heterochromatisation.

Figure 1: DNA methylation induces Histone de-acetylation, modification which characterizes histones in both heterochromatin and repressed euchromatin. MeCP2 specifically binds to methylated DNA, and recruits an HDAC which de-acetylates histones (Ac= Acetyl; Me= Methyl; MeCP2= Methyl-CpG binding Protein 2; HDAC= Histone De-Acetylase).

However, the methylation of DNA is not indispensable for the formation of heterochromatin. It could be an element involved in stabilisation, as has been shown for the facultative HC of the inactive X. Indeed, in marsupials, the inactive X is not methylated and is much less stable than in eutherian mammals.

3) Regular organisation of nucleosomes

We have seen that sequences of prokaryotic DNA inserted into eukaryotes have the ability to be methylated and can induce the formation of heterochromatin. Heterochromatisation may not, however, depend solely on the methylation of the CpGs contained in the DNA. A study of the chromatin of different transgenes digested by a micrococcal nuclease

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -290- provided interesting results. The chromatin of a transgene inserted into constitutive HC revealed a very regular organisation of the nucleosome that was much more regular than the organisation revealed by the same transgene inserted into an euchromatic region. It appears that this regularity of the structure is able either to take on a particular conformation or to be recognised by specific proteins, and, in this way, can promote the formation of heterochromatic structures.

4) Hypo-acetylation of Histones

We have seen that hypo-acetylation of histones is a characteristic of silent chromatin, whether it is heterochromatin or not. In vitro, the modification of the acetylation of the histones has a direct effect on the stability and compaction of the nucleosomes. Thus, blocking the de-acetylation of the histones by adding trichostatine A induces hyper-acetylation of the histones, which causes a more open chromatin structure. The mechanism involved is simple: in the N-terminal tail of the histones, the basic amino-acids such as lysine are positively-charged at cellular pH and therefore interact with the negative charges of the DNA phosphates.

• Acetylation of the lysines removes the positive charge from the histones, thus reducing the force of attraction with the DNA and leading to a wider opening of the chromatin. • In contrast, de-acetylation of the lysines restores the positive charges and thus promotes a close attraction between the histones and the DNA, leading to a condensed chromatin structure.

Hypo-acetylation of the histones is not the only modification of the N-terminal tails of the histones that characterises heterochromatin. Three other modifications have been shown to be more specifically linked to silencing: the phosphorylation of serine 10 of histone H3, the acetylation of lysine 12 of histone H4 and the methylation of lysine 9 of histone H3 (H3-K9). We will present the last of these modifications in more detail.

5) Methylation of H3-K9

Methylation of the histone H3 on lysine 9 is an epigenetic modification of histones that has recently been shown to be involved in the process of heterochromatinisation. This has been demonstrated not only in constitutive HC but also on the inactive X. The enzyme responsible for the methylation of H3-K9 in constitutive HC is the histone methyltransferase SUV39H1.

• On lysine 9 of H3, acetylation and methylation appear to be mutually exclusive. In Drosophila, therefore, the methyltransferase Suv39h is physically and functionally associated with a histone de-acetylase, suggesting a single molecular mechanism that allows the direct conversion of an acetylated lysine 9 into a methylated lysine 9.

• In addition, the methylation of H3-K9 creates a high-affinity binding site for the heterochromatin protein HP1. Co-immuno precipitation of Suvar39h with HP1

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -291- suggests a heterochromatinisation mechanism based on the interaction of these two proteins and lysine 9. Nevertheless, the HP1 protein certainly acts in different ways in the formation of heterochromatin, since it is able to bind to histone 3 and histone H1, even when their N-terminal tails have been removed.

• Lastly, in Neurospora crassa, it has recently been shown that methylation of H3-K9 can cause methylation of DNA. The model proposed is as follows: a histone methyltransferase, characterised by a SET domain, such as Suvar39h, would methylate H3-K9 and induce the binding of a specific heterochromatin protein, such as HP1. The HP1 protein would then recruit a DNA methyl transferase (DNMT), which would methylate the DNA, thus stabilising the inactive state of the chromatin (Figure 2).

Figure 2: Histone H3-K9 methylation induces DNA methylation, modification which characterizes DNA in heterochromatin and repressive euchromatin. SUVAR39H is a methyltransferase which specifically methylates the Lysine 9 of histone H3. Such a methylation creates a binding site for the Heterochromatin Protein HP1 which recruits a DNA methyl transferase, capable to methylate the CpG in DNA (Me= Methyl; Methyl H3-K9= Methyl on Lysin 9 of Histone H3; HP1=Heterochromatin Protein 1; DNMT=DNA Methyl transferase).

6) HP1 proteins

Many different heterochromatin proteins are to be found in mammals, and at the present time little is known about them. The HP1 proteins do appear, however, to have a particular role in the organisation of heterochromatin. Studies of the

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -292- variegation by position effect (PEV effect) in Drosophila and studies of transgenes in Drosophila and mouse have allowed a better understanding of the role of HP1 proteins.

• In Drosophila, the HP1 protein is coded for by the Su(var)205 gene, which is a suppresser of variegation that can modify the PEV effect. The variegation by position effect can be described as follows: genes that are normally localised in active euchromatin are, following a rearrangement of chromosomes, placed close to a centromeric region that is heterochromatic. This change in the position of the euchromatin has three consequences. The first is that the structure is modified to become much more compact. The second is the association of the newly translocated chromatin with HP1 proteins that are normally confined to centromeres. The third consequence is the repression of the genes contained in the translocated chromatin. • In mouse, the insertion of a transgene close to the centromere may have similar consequences, with modification of the chromatin structure, the appearance of HP1 proteins and repression of the transgene. It is interesting to note that even where a transgene is repressed, not as a result of a centromeric effect but as a result of its presence in multiple copies, HP1 proteins are also found to be associated with the repressed chromatin.

In all cases, HP1 proteins or their homologues appear to be an essential link in the formation of heterochromatin. These heterochromatin-specific proteins could have the role of chromatin domain organisers. The HP1 proteins thus appear to be able to recognise particular structures that are created by the pairing and/or the association of repeated DNA sequences. In addition, they appear to be able to establish secondary interactions with a large number of other proteins. The HP1 proteins are perfectly adapted for such interactions, as they have two domains of protein/protein interaction, the chromodomain (CD) and the chromoshadow domain (CSD).

7) Nuclear RNAs

It is already well established that certain nuclear RNAs are able to contribute to the formation of facultative HC. The transcripts of the XIST (X inactive Specific Transcripts) gene are nuclear RNAs that have an essential role in the facultative inactivation of one X chromosome, which occurs in the somatic cells in female mammals. This XIST RNA is necessary for the initiation of X inactivation, but not its maintenance. Other nuclear RNAs, such as H19, have been shown to be involved in the regulation of genes that are subject to genomic imprinting. Some recent studies in mouse have suggested that nuclear transcripts may also be involved in the formation of constitutive HC. In mouse, as in most other species, the centromeric HC is particularly stable. It is characterised by the presence of a high concentration of methylated H3-K9 histone and heterochromatic HP1 proteins, which co-localise in the nuclei with regions strongly stained with DAPI. However, incubation of permeabilised mouse cells with RNAse A causes rapid de-localisation of the HP1 and methylated H3-K9 signals, in relation to the heterochromatin foci. These data suggest that a nuclear RNA may be an essential structural component of constitutive HC. The RNA may either facilitate compaction of the centromeric HC or may serve as an additional binding site for the proteins that associate with the chromatin.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -293- Surprisingly, the treatment with RNAse A does not alter the methylated H3-K9 signals at the level of the Barr body. In fact, on the inactive X chromosome, the methylation of H3-K9 does not appear to lead to the binding of HP1 proteins. This suggests that the facultative heterochromatinisation of the inactive X may require a different mechanism to come into play from that of constitutive HC.

V FUNCTIONS OF HETEROCHROMATIN The precise role of heterochromatin in the human genome long remained a mystery, as its frequent polymorphisms did not appear to have any functional or phenotypic effect.

1) Role of HC in the organisation of nuclear domains

• Studies of the organisation of the nucleus have shown that heterochromatin and euchromatin occupy different domains. HC is usually localised in the periphery of the nucleus and is attached to the nuclear membrane. In contrast, the active chromatin occupies a more central position. • The preferential localisation of HC to the periphery of the nucleus and, in particular, against the nuclear membrane, may be due to the characteristic properties of the protein HP1. This heterochromatin protein interacts specifically with the B lamin receptor, which is an integral component of the inner membrane of the nucleus. • This organisation also has functional consequences. The peripheral localisation of HC concentrates the active elements towards the centre of the nucleus, allowing the active euchromatin to replicate and be transcribed with maximum efficiency. • The fact that HC is "gregarious", and that it tends to agglutinate, may give rise to similar functional consequences.

2) Role of HC in the centromeric function

In most eukaryotes, the centromeres are loaded with a considerable mass of heterochromatin. It has been suggested that centromeric HC is necessary for the cohesion of sister chromatids and that it allows the normal disjunction of mitotic chromosomes.

• It is generally believed that the presence of centromeric HC is important for centromeric function. Thus, in certain organisms which have large blocks of centromeric HC, it has not been possible to identify a specific DNA sequence that defines the centromere itself. Moreover, in the yeast Schizosaccharomyces pombe, the homologue of the HP1 protein Swi6 is absolutely essential for efficient cohesion of sister chromatids during cell division. • However, experiments involving the deletion of satellite DNA show that a large region of satellite DNA repeats is indispensable for the correct functioning of the centromere.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -294- • In an attempt to synthesise all of the above observations, a hypothesis for the function of centromeric HC has been put forward; it may, de facto, create a compartment by increasing the local concentration of the centromeric histone variant, CENP-A, and by promoting the incorporation of CENP-A rather than the histone H3 during replication.

3) Does centromeric HC act as a transporter?

Many proteins have been shown to be associated with centromeric HC, in particular on metaphase chromosomes. It can be assumed that certain proteins that must be present and functional at the very beginning of the G1 phase will not be able to be synthesised due to a lack of time. Following this hypothesis, binding to the centromere would be an ideal means for such proteins to traverse cell division unhindered, in order to be available at the beginning of G1.

4) Role of HC in gene repression (epigenetic regulation)

Gene expression may be controlled at two levels:

• Firstly, at the local level, which is transcription control. Transcription is directly controlled by the formation of local transcription complexes. This level involves relatively small DNA sequences (100 bp) linked to individual genes. • Transcription may also be controlled at a more global level, in which case it is the transcriptability that is controlled. This level involves much larger sequences that represent a large chromatin domain. Such a domain can have one of two states: an active state, which is sensitive to endonucleases, and an inactive state, which is insensitive.

Heterochromatin appears to be involved in controlling the transcriptability of the genome. Genes that are usually located in the euchromatin can, therefore, be silenced when they are placed close to a heterochromatic domain.

• Mechanism of inactivation in cis: Following a chromosomal rearrangement, a euchromatic region containing active genes may be juxtaposed with a heterochromatic region. Where the rearrangement removes certain normal barriers that protect the euchromatin, the heterochromatic structure is able to propagate in cis to the adjacent euchromatin, thus inactivating the genes contained therein. This mechanism has been observed in position effect variegation (PEV) in Drosophila and also in the inactivation of certain transgenes in mouse. It is associated with a modification of the structure of the newly repressed euchromatin that involves the HP1 proteins, characteristic of heterochromatin.

• Mechanism of inactivation in trans: During cell differentiation, certain active genes are likely to be transposed into a heterochromatic nuclear domain, thus causing them to become inactive.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -295- Such a mechanism has been proposed as an explanation for the co- localisation in lymphocyte nuclei of the protein IKAROS and the target genes of which it controls the expression with blocks of centromeric heterochromatin. Thus, target genes could be repressed by a mechanism of inactivation in trans that propagates from the heterochromatin towards the adjacent euchromatin. Another hypothesis is that the protein IKAROS first inactivates the target gene by binding to its promoter and then transposes it into a heterochromatic nuclear domain in order to stabilise the inactivation.

VI HETEROCHROMATIN DISEASES

1) Diseases of the constitutive heterochromatin

These diseases are generally the result of an alteration in the process of cell differentiation.

• They may be constitutional, as in the case of the ICF and Roberts syndromes: The ICF syndrome associates Immunodeficiency, Centromeric instability and Facial anomalies. It is a rare recessive disease that is linked to mutations of the gene DNMT3B, a DNA methyl transferase localised on the long arm of chromosome 20 (Xu et al 1999). The chromosomal anomalies mimic the anomalies obtained with 5- Azacytidine, which is a demethylating agent. Naturally, it is the satellite DNAs that are rich in G-C that are demethylated, that is to say, DNA satellites II and III, and, to a lesser extent, satellite I. Consequently, it is mainly the secondary constrictions of chromosomes 1 and 16 that present an instability. Decondensation of the secondary constrictions alters the normal segregation of the sister chromatids, which explains the formation of multiradial figures, deletions, micronuclei, etc. The centromeric HC that is rich in alpha-satellite DNA, then rich in A-T bases is not affected by this instability.

• They may be acquired, then associated with various types of cancer. Anomalies of the constitutive heterochromatin, involving either the DNA or the heterochromatin proteins, have been found in many types of cancer. o In particular, non-Hodgkin's lymphoma and multiple myeloma have been shown to be associated with anomalies of the secondary constriction of chromosome 1, these anomalies being similar to those observed in the ICF syndrome. This observation strongly suggests that an anomaly of methylation could affect the satellite DNA in these acquired pathologies. Indeed, it has been shown that there is a global hypomethylation of the genome, associated, in particular, with a hypomethylation of DNA satellite II. The hypomethylation is generally correlated with a worsening of the phenotype. It may be that the tumour and oncogenesis progression are linked to an imbalance of genes that results from rearrangements involving the long arm of chromosome 1 or chromosome 16.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -296- o In metastatic breast cancer, it has been shown that there is a decrease in the HP1 alpha protein, which is a protein that is usually localised in the heterochromatic regions of the chromosomes.

2) Diseases of the facultative heterochromatin

• They can result from a defect in the inactivation of an X chromosome in female somatic cells. Such a defect may, in particular, result from a mutation in the XIST gene that is essential for initiating the process of inactivation on the X chromosome. It may lead to the expression of an X-linked recessive disease in females.

• They can result from a defect in the condensation of the sex vesicle in male germ cells, leading to an hypofertility or a sterility due to pachytene arrest of the meiosis.

VII CONCLUSION In conclusion, although heterochromatin is apparently amorphous and isolated at the periphery of the nucleus, it appears to have an absolutely essential role in the organisation and function of the genome. Throughout this review we have mainly presented the characteristics linked with heterochromatin, be it constitutive or facultative. We have shown that the properties of constitutive HC, despite the presence of satellite DNA, are not fundamentally different from those of facultative HC. It therefore seems clear that the mechanisms involved in facultative heterochromatinisation, which are epigenetic mechanisms, are the same mechanisms that intervene in the repression of euchromatin in general.

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Atlas Genet Cytogenet Oncol Haematol 2003; 2 -298- 26. Schmid M, Vogel W, Krone W (1975) Attraction between centric heterochromatin of human chromosomes. Cytogenet Cell Genet 15(2): 66-80. Medline 27. Solari AJ (1980) Synaptosomal complexes and associated structures in microspread human spermatocytes. Chromosoma 81(3): 315-37. Medline 28. Tamaru H, Selker EU (2001) A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414 (6861): 277-83. Medline 29. Therkelsen AJ, Nielsen A, Kolvraa S (1997) Localisation of the classical DNA satellites on human chromosomes as determined by primed in situ labelling (PRINS). Hum Genet 100 (3-4): 322-6. Medline 30. Trinh LA, Ferrini R, Cobb BS, Weinmann AS, Hahm K, Ernst P, Garraway IP, Merkenschlager M, Smale ST (2001) Down-regulation of TDT transcription in CD4(+)CD8(+) thymocytes by Ikaros proteins in direct competition with an Ets activator. Genes Dev 15(14):1817-32. Medline 31. Wallrath LL, Elgin SC( 1995) Position effect variegation in Drosophila is associated with an altered chromatin structure. Genes Dev 9 (10): 1263-77. Medline 32. Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Pequignot E (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402(6758): 187-91. Medline

Contributor(s) Written 01- Marie-Geneviève Mattei, Judith Luciani 2003

Citation This paper should be referenced as such : Mattei MG, Luciani J . Heterochromatin, from Chromosome to Protein. January 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Deep/ HeterochromatineDEEP.html

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -299- Atlas of Genetics and Cytogenetics in Oncology and Haematology

The WNT Signaling Pathway and Its Role in Human Solid Tumors

Lin Thorstensen and Ragnhild A. Lothe

Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway

To whom correspondence should be addressed: Dr. Lin Thorstensen, Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, N-0310 Oslo, Norway. Tel: +47 22934431, Fax: +47 22934440, E-mail: [email protected]

April 2003

The current knowledge of the canonical Wingless-type MMTV integration site family (Wnt) signaling pathway emerges from studies of the Wingless (Wg) pathway in Drosophila melanogaster and the Wnt pathway in Xenopus laevis, Caenorhabditis elegans (C. elegans) as well as in mammalians. The Wnt signaling pathway is evolutionary conserved and controls many events during the embryogenesis. At the cellular level this pathway regulates morphology, proliferation, motility and cell fate. Also during tumorigenesis the Wnt signaling pathway has a central role and inappropriate activation of this pathway are observed in several human cancers (Spink et al., 2000).

In the first part of this review, central Wnt pathway proteins and their binding partners will be described, whereas the second part will focus on genetic and epigenetic alterations of WNT components in human solid tumors.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -300-

List of abbreviations:

Ala Alanine APC Adenomatous polyposis coli Arm Armadillo APC-stimulated guanine nucleotide Asef r exchange factor -TrCP b-transducin repeat-containing protein CBP CREB binding protein CK1, 2 Casein kinase 1 and 2 CtBP C-terminal binding protein DIX Dishevelled homologous Dkk Dickkopf DLG Disc large tumor suppressor protein Dsh/Dvl Dishevelled FAP Familial adenomatous polyposis coli Frequently rearranged in advanced T- FRAT cell lymphomas Fz Frizzled GBP GSK-3 binding protein GSK-3 Glycogen synthase kinase-3 HMG High mobility group HCC Hepatocellular carcinoma ICAT Inhibitor of b-catenin and TCF-4 ILK Integrin-linked kinase LEF Lymphoid enhancing factor Lgs Legless Low density lipoprotein receptor related LRP protein Met Methionine MMTV Mouse mammary tumor virus MSI Microsatellite instability NES Nuclear export signal NLK Nemo-like kinase NLS Nuclear localization signal PHD Plant homology domain Pin-1 Peptidyl-propyl cis-trans isomerase-1 PI-3K Phosphatidylinositol-3 kinase

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -301- PP2A Protein phosphatase 2A Pro Proline Pygo Pygopus RGS Regulators of G-protein signaling SAMP Ser-Ala-Met-Pro SARP Secreted apoptosis-related protein Ser Serine sFRP secreted frizzled-related protein Tak TGFb-activated kinase TCF T-cell factor TGF Transforming growth factor Thr Threonine TLE Transducin-like enhancer of split Wg Wingless WIF-1 Wnt-inhibitory factor-1 Wingless-type MMTV integration site Wnt family member

The Wnt signaling pathway

The Wnt signaling pathway is essential in many biological processes and numerous studies of this pathway over the last years have lead to the identification of several novel components. Nevertheless, many of the mechanisms involved in activation or inactivation of this particular pathway still remains to be elucidated. The pathway with or without a Wnt signal is schematically presented in Figure 1.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -302-

Figure 1. Schematic presentation of the Wnt pathway

In the presence of a Wnt ligand, if not inhibited by secreted antagonists, the Wnt ligand binds a frizzled (Fz)/low density lipoprotein receptor related protein (LRP) complex, activating the cytoplasmic protein dishevelled (Dsh in Drosophila and Dvl in vertebrates). Precisely how Dsh/Dvl is activated is not fully understood, but phosphorylation by casein kinase 1 (CK1) and casein kinase 2 (CK2) have been suggested to be partly responsible (Willert et al., 1997; Sakanaka et al., 1999; Amit et al., 2002). Dsh/Dvl then inhibits the activity of the multiprotein complex (b-catenin-Axin- adenomatous polyposis coli (APC)-glycogen synthase kinase (GSK)-3 ), which targets -catenin by phosphorylation for degradation by the

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -303- proteasome. Dsh/Dvl is suggested to bind CK1 and thereby inhibiting priming of -catenin and indirectly preventing GSK-3 phosphorylation of - catenin (Amit et al., 2002). Upon Wnt stimulation, Dvl has also been shown to recruit GSK-3 binding protein (GBP) to the multiprotein complex. GBP might titrate GSK-3 from Axin and in this way inhibits phosphorylation of - catenin. Finally, sequestration of Axin at the cell membrane by LRP has been described (Mao et al., 2001b). The overall result is accumulation of cytosolic -catenin. Stabilized -catenin will then translocate into the nucleus and bind to members of the T-cell factor (Tcf)/Lymphoid enhancing factor (Lef) family of DNA binding proteins leading to transcription of Wnt target genes.

In the absence of a Wnt ligand, Axin recruits CK1 to the multiprotein complex causing priming of -catenin and initiation of the -catenin phosphorylation cascade performed by GSK-3 . Phosphorylated -catenin is then recognized by -transducin repeat-containing protein ( -TrCP) and degraded by the proteaosome, reducing the level of cytosolic -catenin.

1. Extracellular inhibitors

At least three classes of Wnt antagonists are reported in Xenopus, all with human homologues, however, none of them have been identified in Drosophila or C. elegans. The first class, secreted frizzled-related proteins (sFRPs), are also called secreted apoptosis-related proteins (SARPs) due to their effect on cell sensitivity to pro-apoptotic stimuli (Melkonyan et al., 1997). They contain a cysteine-rich domain with similarity to the ligand-binding domain of the Fz transmembrane protein family, but lack the 7- transmembrane part that anchors Fz proteins to the plasma membrane (Rattner et al., 1997). The sFRPs thus compete with the Fz proteins for binding to secreted Wnt ligands and antagonize the Wnt function. However, a contradictory effect of the sFRPs has been described, in which the sFRPs enhance the Wnt activity by facilitating the presentation of the ligand to the Fz receptors (Uthoff et al., 2001). Three human homologues are identified, SARP1-3, but they show distinct expression pattern (Melkonyan et al., 1997).

Wnt-inhibitory factor-1 (WIF-1) represents the second class of secreted Wnt antagonists, and in Xenopus WIF-1 binds to Wnt proteins and inhibits their activities by preventing access to cell surface receptors (Hsieh et al., 1999). A human homologue, located at chromosome 12, is identified (Hsieh et al., 1999). The third type of secreted antagonists, Dickkopf (Dkk), includes four known human proteins, DKK1-4 (Krupnik et al., 1999). In Xenopus, Dkk1 does not inhibit Wnt ligands directly, but interacts with the Wnt co- receptor, LRP, and prevents formation of an active Wnt-Fz-LRP receptor complex (Mao et al., 2001a). Recently, it was found that Kremen1 and Kremen2 worked as Dkk receptors (Mao et al., 2002) and a ternary complex between Kremen2, Dkk1 and LRP6lead to endocytosis and thus removal of LRP6 from the plasma membrane

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -304- (Mao et al., 2002). Surprisingly, Dkk2 was reported to induce Wnt signaling by working synergistically with the Fz family rather than inhibiting Wnt stimulation(Wu et al., 2000).

2. Ligands and receptors

Wnt ligands belong to a family of proto-oncogenes expressed in several species ranging from the fruit fly to man. This large family of secreted glycoproteins is considered one of the major families of signaling molecules. The first Wnt gene, mouse Int-1, was identified by its ability to form mammary tumors in mice when activated by integration of the mouse mammary tumor virus (MMTV)(Nusse and Varmus, 1982). Int-1 was later renamed Wnt-1 due to the relationship between this gene and the Wg gene in Drosophila (Nusse et al., 1991). At present, 19 human WNT genes are characterized (http://www.stanford.edu/~rnusse/wntwindow.html). Although the individual members of this family are structurally related, they are not functionally equivalent and each may have distinct biological properties (Dimitriadis et al., 2001).

In Drosophila, the Fz genes play an essential role in development of tissue polarity. The Fz genes code for seven-transmembrane proteins and lines of evidence showing that Fz proteins work as receptors for Wg in Drosophila exist (Bhanot et al., 1996). Several mammalian homologues have been identified (http://www.stanford.edu/~rnusse/wntwindow.html). Both the extracellular cysteine rich domain and the transmembrane segment are strongly conserved, but nevertheless, the Fz proteins differ in both function and ligand specificity (Wang et al., 1996). Although it is known that the Wnts interact with the Fz receptor, the mechanism of Fz signaling is not fully understood (Uthoff et al., 2001).

In Drosophila, Xenopus, and mouse the Arrow (Drosophila)/LRP (in vertebrates) is required during Wnt signaling, possibly by acting as a co-receptor for Wnt (Pinson et al., 2000; Tamai et al., 2000; Wehrli et al., 2000). The LRP gene encodes a long single-pass transmembrane protein, and the extracellular domain binds Wnt directly making a ternary complex with the Fz receptor (Tamai et al., 2000). Recently it was observed that the intracellular part of LRP binds Axin (Mao et al., 2001b). The authors hypothesized that Fz-Wnt-LRP complexes and subsequently LRP recruits Axin to the complex, thereby inactivating Axin leading to release of -catenin from the multiprotein complex (see later) and consequently transcription of downstream Wnt target genes. Two mammalian homologues have been described, LRP5 (Hey et al., 1998) and LRP6 (Brown et al., 1998).

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -305- 3. Downstream of the receptor complex

Dsh in Drosophila and Dvl in vertebrates encode a cytoplasmic phosphoprotein and is a positive mediator of Wnt signaling (Klingensmith et al., 1994). In the human genome, three homologues have been described, DVL1-3 (Pizzuti et al., 1996; Bui et al., 1997). Dsh/Dvl works downstream of Fz receptor, but upstream of -catenin (Uthoff et al., 2001). However, its exact mechanism of action remains unknown, but several binding partners have been detected (Figure 2).

Figure 2. Dsh/Dvl and binding partners

The dishevelled homologous (DIX) domain of Dvl binds Axin. This binding inhibits Axin promoted GSK-3 dependent phosphorylation of -catenin (Kishida et al., 1999).

In Drosophila, CK2 works as a positive mediator of Wg signaling by interacting with the basic domain of Dsh and subsequently activates it (by phosphorylation)(Willert et al., 1997).

Upon Wnt stimulation, Dsh/Dvl binds CK1. This binding probably inhibits phosphorylation priming of the Serine (Ser) 45 site in -catenin causing stabilization of -catenin and activation of the Wnt pathway (Sakanaka et al., 1999; Amit et al., 2002). However, the exact mechanism of this event is yet unknown. In the absence of a Wnt signal, CK1 associates and cooperates with Axin, probably through diversin (see below). This drives the phosphorylation and degradation cascade of -catenin, and subsequently inhibits the Wnt signaling pathway (Amit et al., 2002).

During Wnt stimulation in Xenopus, GBP interacts with the PDZ domain of Dvl (Li et al., 1999). The name PDZ derives from three proteins that contain repeats of the same type as found in this domain: mammalian postsynaptic density protein, PSD-95, Drosophila discs-large tumor suppressor, Dlg, and the mammalian tight junction (zonula occludens) protein, ZO-1. As mentioned, Dvl also interacts with Axin. Both GBP and Axin bind GSK-3 , however these two components share overlapping binding sites on GSK-3 and thus compete in binding to this protein. One theory suggests that in the presence of a Wnt signal, Dvl recruits GBP to the multiprotein complex. GBP then titrates GSK-3 from Axin leading to accumulation of -catenin in the cytoplasm (Fraser et al., 2002). The human homologue of GBP is frequently

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -306- rearranged in advanced T-cell lymphomas (FRAT). Newly, FRAT/GBP was shown to contain a nuclear export sequence, leading to nuclear export of itself as well as the bound GSK-3 . Thus, FRAT/GBP is involved in regulating the accessibility of cytoplasmic GSK-3 (Franca-Koh et al., 2002). Two human family members, FRAT-1 and FRAT-2, are identified (Jonkers et al., 1997; Saitoh et al., 2001), but none is described in Drosophila.

In the fly, the naked protein binds Dsh and downregulates its activity. The expression of Naked is induced by Wg, indicating a negative feedback mechanism (Zeng et al., 2000).

4. The multiprotein complex

The stability of -catenin (encoded by the gene CTNNB1) is regulated by a multiprotein complex consisting of -catenin, Axin/Conductin, APC, and GSK-3 (Schwarz-Romond et al., 2002). In this scaffolding complex, GSK-3 phosphorylates primed -catenin, thus marking - catenin for ubiquitylation and subsequent proteasome degradation. During the last years, several novel players that interact with the components of the multiprotein complex have emerged. Still, the exact mechanisms of action of the multiprotein complex need further clarification.

-catenin

-catenin was first described in humans as a protein which interacts with the cytoplasmic domain of E-cadherin and with -catenin, anchoring the cadherin complex to the actin cytoskeleton (Kemler and Ozawa, 1989). Then, the homology between -catenin and the Armadillo (Arm) of Drosophila and -catenin in Xenopus lead to the discovery of an additional role for mammalian -catenin, namely as the key mediator of Wnt signaling (McCrea et al., 1991; Gumbiner, 1995).

The primary structure of -catenin comprises an amino-terminal domain of approximately 130 amino acids, a central region of 12 imperfect repeats of 42 amino acids known as arm repeats (since they show homology with repeats found in the Arm protein of Drosophila), and a carboxy-terminal domain of 110 amino acids. The amino- terminus of -catenin is important for regulating of its stability, whereas the carboxyl terminus works as a transcriptional activator domain (Willert and Nusse, 1998).

Interestingly, plakoglobin, also called -catenin, shares overall 70% amino acid identity with -catenin and as much as 80% within the arm repeat domain (Huber and Weis, 2001). Plakoglobin binds E-cadherin, -catenin, APC, Axin and Tcf/Lef transcription factors, and is involved

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -307- in cell adhesion as well as Wnt signaling. However, differences between -catenin and plakoglobin in these processes exist (Kolligs et al., 2000).

-catenin activity is controlled by a large number of binding partners that affect the stability and localization of -catenin (Figure 3).

Figure 3. -catenin and binding partners

Two ubiquitin-mediated degradation systems are involved in the catabolism of -catenin. Both F-box proteins, -TrCP and Ebi, recognize and bind to the same sites on the N-terminal domain of -catenin (Polakis, 2001). However, unlike -TrCP, Ebi probably does not require phosphorylation of -catenin for recognition. Ebi works in complex with SIAH-1, a TP53 induced protein, linking activation of TP53 to the degradation of -catenin (Liu et al., 2001; Matsuzawa and Reed, 2001). Both degradation systems require an intact APC protein (Polakis, 2001).

GSK-3 sequentially phosphorylates threonine (Thr) 41, Ser 35, and Ser 33 of -catenin after -catenin has been primed (phosphorylated at Ser 45) by CK1 (Amit et al., 2002; Schwarz-Romond et al., 2002; Liu et al., 2002).

Binding of -catenin to the N-terminal region of -catenin (Nagafuchi et al., 1994) and E-cadherin to the arm repeat (Huber and Weis, 2001) connects - catenin to cell adhesion.

The arm repeat domain of -catenin mediates binding of cadherins (Hulsken et al., 1994; Pai et al., 1996), APC (Hulsken et al., 1994; Rubinfeld et al., 1995), Axin (Behrens et al., 1998; Ikeda et al., 1998), and Tcf/Lef family of transcription factors (Behrens et al., 1996; van de et al., 1997). E- cadherin, APC and Tcf/Lef interact with this domain of -catenin in an overlapping and mutually exclusive manner (Willert and Nusse, 1998).

In Drosophila, Legless (Lgs) and Pygopus (Pygo) have recently been shown to be required for Arm to function as a transcriptional co-activator in the Wg signaling pathway (Kramps et al., 2002). Lgs encodes the homologue of

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -308- human BCL-9, whereas Pygo codes for a PHD (plant homology domain) finger protein and two human homologues have been identified, hPYGO1 and hPYGO2 (Kramps et al., 2002). Lgs/BCL-9 is shown to bind the arm repeats of Arm/ -catenin and work as a linker molecule between Pygo and the Arm/ -catenin - Pan/Tcf complex in the nucleus leading to transcription of Wg/Wnt target genes (Kramps et al., 2002). The exact mechanism of action of Pygo remains unknown.

Peptidyl-propyl cis-trans isomerase 1 (Pin1) binds a phosphorylated Ser- Proline (Pro) motif next to the APC binding site in -catenin and inhibits interaction between APC and -catenin, consequently acting as a positive regulator of Wnt signaling (Ryo et al., 2001).

In Xenopus, the transactivating domain of -catenin interacts with CREB binding protein (CBP) and these synergistically stimulate transcription of Wnt target genes (Takemaru and Moon, 2000).

In mouse studies, inhibitor of -catenin and TCF-4 (ICAT) binds the C- terminal domain of -catenin and inhibits its interaction with TCF-4. - catenin-TCF-4 mediated transactivation of Wnt target genes is then repressed (Tago et al., 2000).

APC

The first hint of the mode of action of APC came from studies showing that APC binds -catenin (Rubinfeld et al., 1993; Su et al., 1993). Later it has been demonstrated that APC plays a central role in regulating the -catenin level in the Wnt signaling pathway in addition to be involved in cell migration, cytoskeleton regulation, and chromosome segregation (Fodde, 2003), functions of APC that will not be dealt with in this paper.

APC encodes a large protein consisting of several distinct conserved domains (Groden et al., 1991), interacting with a number of different proteins (Figure 4).

Figure 4. APC and binding partners

The amino-terminal end of APC contains heptad repeats involved in

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -309- oligomerization of APC (Joslyn et al., 1993).

The holoenzyme, protein phosphatase 2A (PP2A), comprises three subunits, the structural- (A), the regulator- (B), and catalytic- (C) subunit. APC, like -catenin, harbors arm repeats to which the regulatory subunit of PP2A, B56, binds (Seeling et al., 1999). In Xenopus, the PP2A holoenzyme (containing B56) is present in the -catenin degradation complex, and PP2A is suggested to dephosphorylate and activate GSK-3 , leading to degradation of -catenin and inhibition of Wnt signaling (Li et al., 2001a).

The arm repeats of APC also bind to APC-stimulated guanine nucleotide exchange factor (Asef) and enhances the interaction between Asef and Rac, a member of the Rho family of small GTPases. This further modulates the actin cytoskeleton and influence cell adhesion and cell motility (Kawasaki et al., 2000).

Three 15-amino acid repeats and seven 20-amino acid repeats within APC are known to bind -catenin (Rubinfeld et al., 1993; Su et al., 1993). Phosphorylation of APC by GSK-3 increases the negative charge on APC and strengthens the interaction between APC and the positively charged arm repeat domain of -catenin (Oving and Clevers, 2002). Down regulation of -catenin requires at least three of the seven 20 amino acid repeats to be intact (Rubinfeld et al., 1997).

Three Ser-Alanine (Ala)-Methionine (Met)-Pro (SAMP) motifs are located within the 20 amino acid repeats of APC and these mediate binding to Axin (Behrens et al., 1998).

APC also contains two intrinsic nuclear localization signals (NLSs) located in the middle and C-terminal region of APC (Zhang et al., 2000) and at least two intrinsic nuclear export signals (NESs), located near the amino terminus (Neufeld et al., 2000a; Henderson and Fagotto, 2002). Recently, it was shown that APC binds nuclear -catenin and stimulates its nuclear export and subsequently its cytoplasmic degradation (Neufeld et al., 2000b). Phosphorylation sites near the NLS2 site were shown to be critical for regulation of APC’s nuclear distribution (Zhang et al., 2001).

A basic domain in the C-terminal region of APC binds microtubules directly, inducing stabilization of their ends (Zumbrunn et al., 2001). APC also contains a binding site for EB1, another microtubuli binding protein, which is required for APC-mediated attachment of microtubules to the chromosomes’ kinetochores, ensuring proper chromosome segregation during mitosis (Su et al., 1995; Kaplan et al., 2001; Fodde et al., 2001). The interaction of APC with microtubules is decreased by phosphorylation of APC by GSK-3 (Zumbrunn et al., 2001).

The C-terminus of APC also interacts with the human homologue of the Drosophila discs-large tumor suppressor protein (DLG) (Matsumine et al., 1996). However the effect of this interaction is not yet fully understood.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -310- Axin

In 1997, Axin, the product of mouse fused locus, was introduced as a novel component in the Wnt signaling pathway (Zeng et al., 1997). Axin works as a scaffold protein involved in forming the multiprotein complex leading to phosphorylation and degradation of -catenin and thereby acts as a negative regulator of Wnt signaling. Later, a homologue of Axin in mouse, Conductin, and in rat, Axil, were identified (Behrens et al., 1998; Yamamoto et al., 1998). Two human homologues also exist, AXIN1(the Axin homologue)(Zeng et al., 1997) and AXIN2(the Conductin/Axil homologue)(Mai et al., 1999). Axin and Conductin share 45% amino acid identity. Interestingly, Axin is homogeneously distributed, whereas Conductin is more selectively expressed in specific tissues (Lustig et al., 2002). Recently, it was shown that Conductin is a downstream target gene of the Wnt pathway and might work in a negative feedback loop controlling Wnt signaling activity (Lustig et al., 2002). TCF binding sites has also been identified in the human homologue, AXIN2 (Leung et al., 2002).

Several components of the Wnt signaling pathway interact with Axin (Figure 5).

Figure 5. Axin and binding partners

APC binds to Axin at a region with significant homology to the regulators of G-protein signaling (RGS) family (Spink et al., 2000).

GSK-3 is recruited to the multiprotein complex by Axin (Behrens et al., 1998) and then phosphorylates Axin and APC and increases their interaction with -catenin (Peifer and Polakis, 2000). Subsequently, primed -catenin bound to Axin and APC (Behrens et al., 1998), is phosphorylated by GSK- 3 , marking -catenin for proteasome degradation.

In Xenopus and cell cultures, diversin (an ankyrin repeat protein) also binds to Axin and recruits CK1 to the multiprotein complex (Schwarz-Romond et al., 2002). Diversin/CK1 and GSK-3 cooperate in -catenin degradation, however diversin and GSK-3 use identical binding sites on Axin suggesting

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -311- that a homodimeric Axin complex is present to perform phosphorylation and degradation of -catenin. One of the Axin molecules binds diversin that recruits CK1, leading to priming of -catenin, whereas the other Axin molecule binds GSK-3 causing phosphorylation of primed -catenin. A closely related diversin gene is identified in humans, ANKRD6 (Schwarz- Romond et al., 2002).

The PP2A catalytic subunit binds Axin (Hsu et al., 1999), and the PP2A holoenzyme works as a negative regulator of Wnt signaling (Li et al., 2001a).

The DIX domain of Axin binds Dsh/Dvl (Kishida et al., 1999) and LRP5, the co-receptor for the Wnt ligand (Mao et al., 2001b). In addition, this domain is necessary for oligomerization of Axin (Kishida et al., 1999). The putative effects of these interactions have been described previously in the text. The DIX domain is essential for degradation of -catenin (Kikuchi, 1999).

GSK-3

GSK-3 , zw3 or shaggy in Drosophila, is a member of the Ser/Thr family of protein kinases. This protein is a key enzyme in the Wnt signaling pathway. As outlined above, GSK-3 phosphorylates primed -catenin prior to proteasome degradation, and it phosphorylates Axin and APC and enhances their interaction with -catenin.

Unlike most protein kinases, GSK-3 is constitutively active and phosphorylation of GSK-3 leads to inhibition of its activity (Manoukian and Woodgett, 2002). Two highly related human homologues are identified, GSK-3 and GSK-3 and these two isoforms are more than 95% identical in the protein kinase catalytic domain (Woodgett, 1990). Consequently, GSK-3 can substitute for many, but not all of the functions of GSK-3 in the Wnt signaling pathway (Manoukian and Woodgett, 2002).

5. Nuclear components

The stabilized cytosolic -catenin will be translocated into the nucleus, but how -catenin enters the nucleus is not yet fully understood. Nuclear -catenin associates with the family of Tcf/Lef transcription factors, and is therefore a key factor for expression of Wnt downstream genes.

Tcf/Lef

The Tcf/Lef proteins are a class of related high mobility group (HMG)- box of transcription factors. Four human homologues of Tcf/Lef have been identified, LEF1, TCF1, TCF3 and TCF4. They all recognize the

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -312- same DNA sequences, however they display tissue specific expression patterns. With Wnt signal, Tcf/Lef acts in a complex with -catenin, BCL-9, Pygo and CBP(see Figure 1) and target genes like c-MYC, cyclin D1, WNT inducible signaling pathway protein (WISP)-3, and matrix metalloproteinase (MMP)-7, are expressed. Without the presence of Wnt stimulation, the Tcf/Lef proteins repress transcription of the Wnt target genes by binding to co-repressors like Groucho and C-terminal binding protein (CtBP).

In Figure 6 the cooperation of Tcf/Lef family members with various proteins are shown.

Figure 6. Tcf/Lef and binding partners

Nuclear -catenin makes a heterodimeric complex with the N-terminal region of Tcf/Lef supplying the complex with a transactivating domain, whereas Tcf/Lef contributes with a DNA-binding domain. Potential co- activators bind to -catenin (Figure 3).

In Xenopus, Smad4, an essential component of the transforming growth factor (TGF) - signaling pathway, interacts with Lef1, making a -catenin- Lef1-Smad4 complex harboring dual DNA recognition specificity. Only target genes containing sites recognized by both the DNA-binding proteins will be transcribed.

At least two different co-repressors bind and inhibit the effect of Tcf/Lef in the absence of nuclear -catenin. One of these is the Groucho (found in Drosophila), which interacts with a histone deacetylase resulting in a “closed” chromatin structure that does not allow transcription. Three human homologues of Groucho are described, transducin-like enhancer of split 1-3 (TLE 1-3). In Xenopus, the second known co-repressor, CtBP, is shown to bind and repress Tcf3 and Tcf4.

TGF -activated kinase (Tak)-1acts upstream of nemo-like kinase (NLK). In vertebrates, NLK co-localizes and phosphorylates Tcfs. This reduces the DNA binding capacity of Tcfs and thereby removes -catenin-Tcf complexes from the promoter region of Wnt target genes.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -313- 6. Wnt target genes

At present more than 50 Wnt target genes have been described in Drosophila and vertebrates. Most of them are listed at: http://www.stanford.edu/~rnusse/wntwindow.html. These are involved in numerous processes, including development, cell proliferation, cell-cell interactions and cell-matrix interactions. The majority of these genes contain Tcf/Lef binding sites in their promoter, however other mechanisms of activation have also been reported. In this review, the target genes will not be described in detail.

Alteration of the Wnt signaling pathway in human solid tumors

Chronic activation of the Wnt signaling pathway has been implicated in the development of a variety of human malignancies, including colorectal carcinomas, hepatocellular carcinomas (HCCs), melanomas and uterine and ovarian carcinomas. Mutations in the regulator genes, CTNNB1, APC and AXIN, as well as in other components of this pathway have been reported. The effect of the various mutations is an increase in the cellular level of -catenin and subsequent transcription of Wnt target genes like c-MYC, cyclin D1 and WISP-1. However, alterations of genes encoding proteins working up-stream of the multiprotein complex have not yet been described in human tumorigenesis, but altered expression has been observed for some of these components. Neither has GSK-3 been reported mutated in human cancers. This might be explained by the central role of GSK-3 also in pathways other than the WNT pathway and mutation in this gene may be incompatible with cell viability. Alternatively the closely related gene, GSK-3 may substitute for loss of GSK-3 and inactivation of both genes is unlikely in tumor development.

An overview of the different WNT components found mutated in human tumors is presented in Figure 7, followed by a detailed discussion.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -314- a)

Figure 7. Wnt genes mutated in human solid tumors a) Wnt is present, b) No Wnt stimulation. Genes marked with a black circle are found mutated in human solid tumors (for details see the text).

-catenin

The CTNNB1 gene encodes -catenin. Exon 3 of this gene is hot spot for mutation in human tumors. This exon encodes the critical Ser/Thr residues, which are sites for priming by CK1 (Ser 45) and phosphorylation by GSK-3 (Ser 33, 37 and Thr 41) and thus the recognition site of -TrCP marking -catenin for degradation. Therefore mutations within this exon increase the stability of the -

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -315- catenin protein. Indeed, somatic mutations in exon 3 have been described in a wide variety of human tumors, including colorectal carcinoma, desmoid tumor, endometrial carcinoma, HCC, hepatoblastoma, intestinal carcinoma gastric, medulloblastoma, melanoma, ovarian carcinoma, pancreatic carcinoma, pilomatricoma, prostate carcinoma, squamous cell carcinoma of the head and neck, thyroid carcinoma, and Wilms’ tumor (http://www.stanford.edu/~rnusse/wntwindow.html). In colorectal carcinomas, desmoid tumors and hepatoblastomas an inverse correlation between CTNNB1 mutations (exon 3) and APC mutations are observed. Only two reports, both on colorectal tumors, have examined other exons of CTNNB1 than exon 3. The consequence of mutations outside exon 3 is presently unknown, however the majority of the tumors and cell lines with mutation outside exon 3 also showed mutation in APC. A tendency towards more CTNNB1 mutations in colorectal tumors with microsatellite instability (MSI) than in those without have been reported, however this correlation is not appearent in all studies and are not found in endometrial carcinomas.

Plakoglobin/ -catenin

Plakoglobin is encoded by , which has so far not been found mutated in human primary tumors. Only one gastric carcinoma cell line and one squamous-cell lung carcinoma cell line have been reported with mutations in this gene. Nevertheless, and in contrast to -catenin, plakoglobin induces neoplastic transfomation of rat epithelial cells in the absence of stabilizing mutations. The cellular transformation performed by plakoglobin is also distinct from -catenin in that activation of the proto-oncogene c-MYC is required. Increased nuclear expression of plakoglobin is seen in several human tumors like colorectal carcinomas, endometrial carcinomas, esophageal carcinomas and testicular germ cell tumors. The C-terminal domain, which harbors the transactivating domain, is very different in plakoglobin and -catenin and these two proteins might therefore activate different target genes by recruiting different transcription co-factors to the plakoglobin/TCF and - catenin/TCF complexes.

APC

Patients with familial adenomatous polyposis coli (FAP) harbor a germline mutation in the tumor suppressor gene APC. Germline mutations within different regions of the gene are associated with different disease phenotypes, as for instance mutations in codon 1403 to 1578 are associated with extracolonic manifestations, whereas mutations in codon 78 to 167 and codon 1581 to 2843 are seen in attenuated adenomatous polyposis coli. Although more than 90% of the

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -316- somatic mutations reported in APC are observed in colorectal carcinomas, mutations have also been described in breast carcinomas, desmoid carcinomas, hepatoblastomas, HCCs, intestinal type of gastric carcinomas, medulloblastomas, ovarian carcinomas, pancreatic carcinomas and thyroid carcinomas (http://archive.uwcm.ac.uk./uwcm/mg/search/119682.html). Approximately 80% of sporadic colorectal carcinomas contain mutations in APC. The mutation cluster region, codons 1286-1513, accounts for 10% of the coding region, but harbors 80-90% of all APC mutations. The majority of the mutations lead to a truncated protein, missing some or all of the -catenin binding and down regulation sites, in addition to the AXIN binding sites and thus making APC disable to regulate the -catenin level in the cell. Minimum three of seven 20 amino acid repeats have to be intact for proper degradation of - catenin. However, for nuclear export of -catenin only one of seven 20 amino acid repeats in APC is required. In addition to genetic alterations of APC, inactivation through promoter hypermethylation has been found in a subset of several human malignancies.

AXIN

It has been suggested that AXIN1, which is constitutively expressed, is important for the regulation of the basal activity of the WNT signaling pathway, whereas AXIN2, which is induced in response to increased - catenin levels, rather regulates the duration and intensity of a WNT/ - catenin signal. Biallelic inactivation (mutation and deletion) of the AXIN1 gene has been reported in HCC, implying that AXIN1 acts like a tumor suppressor gene. AXIN1 mutations have also been detected in some endometrioid ovarian carcinomas, medulloblastomas and microsatellite instable colorectal carcinomas. Exon seven of AXIN2 contains four repetitive sequences and these are found mutated in about one fourth of colorectal carcinomas with MSI. An inverse correlation between mutations in AXIN1/AXIN2 and APC or CTNNB1 has been suggested, however some HCCs contain mutations in both AXIN1/AXIN2 and CTNNB1 and a few microsatellite instable colorectal carcinomas have mutations in both AXIN2 and APC. As previously described, the DIX domain of AXIN is essential for the inhibitory effect of this protein on the WNT signaling pathway. The majority of the mutations described so far (both in AXIN1 and AXIN2) are predicted to truncate the protein and probably give rise to a protein lacking a part of or the whole DIX domain.

TCF/LEF

TCF/LEF mRNAs undergo extensive alternative splicing. TCF1 and LEF1 also exhibit alternative promoter usage generating protein

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -317- isoforms that either carry or lack binding sites for -catenin. LEF1 has been suggested as a positive feedback regulator of the Wnt signaling pathway in colorectal carcinogenesis. In these tumors the - catenin/TCF complexes selectively activate one of the promoters in LEF1 leading to expression of a full-length isoform that binds -catenin. It has further been suggested that APC and LEF1 compete for nuclear -catenin and that LEF1 might anchor -catenin in the nucleus by blocking APC mediated nuclear export. On the other hand, upregulation of a dominant negative isoform of TCF1, that do not bind - catenin, has been observed in human colon cancer cell lines with an activated WNT signaling pathway. However, so far TCF4 is the only TCF/LEF family member that has been found mutated in human cancers. TCF4 contains an (A)9 repeat in exon 17 and this repeat is mutated in a subset of colorectal and gastric -carcinomas with MSI. This mutation decreases the proportion of the long TCF4 isoform, which contain two binding domains for the transcriptional co-repressor CtBP and might therefore constitutively activate transcription of WNT target genes. Interestingly, mutation in either APC, CTNNB1 or AXIN1 is observed in the tumors harboring a TCF4 mutation.

b-TrCP

-TrCP is the F-box protein that control degradation of phosphorylated -catenin. Recently, this gene was found mutated in a human prostate cancer cell line and a prostate xenograft. Both alterations were heterozygous, but in vitro studies showed that they rendered the - TrCP protein deficient in -catenin binding and accumulation of nuclear -catenin was observed. Wild type APC and CTNNB1 were seen in both cases suggesting that -TrCP might substitute for APC and CTNNB1 mutations in prostate cancer. Interestingly, increased expression of -TrCP is detected in cells with an activated WNT signaling pathway, indicating that -TrCP is involved in a negative feedback regulation mechanism.

TP53

Cellular responses to TP53 activation include cell-cycle arrest, apoptosis, DNA repair, senescence and differentiation. Approximately 50% of all human cancers show mutation in TP53 (http://www.iarc.fr/p53/Index.html). Newly, a functional cross-talk between TP53 and the WNT signaling pathway was observed. TP53 transactivates SIAH-1 leading to ubiquitin-mediated proteasome degradation of oncogenic (unphosphorylated) -catenin. Presently, it is unknown if TP53 mutations substitute for oncogenic activation of CTNNB1 during tumor development. However, in HCC CTNNB1 mutations and TP53 mutations are mutually exclusive.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -318-

PP2A

The PP2R1Bgene, which encodes the b isoform of the A subunit of PP2A is mutated in 15% of human primary colon tumors. Additionally, some lung cancer cell lines show sequence alterations within this gene. These mutations might destabilize the holoenzyme complex and thus abolish its effect on the WNT signaling pathway.

E-cadherin

The gene encoding E-cadherin, CDH1, is altered in human tumorigenesis by different mechanisms. Germline mutations in CDH1 predispose to hereditary diffuse-type gastric cancer, whereas somatic mutations in CDH1 are demonstrated in several human carcinomas, like diffuse type gastric carcinomas, lobular breast carcinomas, endometrial carcinomas, ovarian carcinomas and signet-ring cell carcinomas of the stomach. Certain tumors that display mutation in one allele of CDH1 also acquire deletion in the other allele, which is consistent with a two-hit mechanism for inactivation. Hypermethylation of the CDH1 promoter has been observed in some primary tumors without identified CDH1 mutations, including human breast, colorectal, gastric, HCC, prostate and thyroid carcinomas. Transcriptional silencing of E-cadherin may also result from aberrant expression of transcription factors that repress its promoter. Examples of such transcription repressors are , SLUG, SIP1 and E12/E47. Interestingly, SNAIL is located to chromosome band 20q13.1, a region frequently amplified in human cancer. In HCC, breast carcinomas, melanoma and oral squamous cell carcinomas, an inverse correlation between SNAIL and E-cadherin expression is observed. Nevertheless, inactivation of E- cadherin does not appear to significantly increase the level of free cytosolic -catenin, probably because the excess of cytoplasmic - catenin rapidly is removed by an intact degradation system. It has been shown that introduction of CDH1 into a cell line lacking E-cadherin and demonstrating constitutively transcription of WNT target genes, help sequester -catenin and thus reduce the transcription of WNT target genes. However, the converse has never been proven. Loss of expression of E-cadherin did not result in constitute -catenin/TCF transcriptional activation.

-catenin

The CTNNA1gene encodes -catenin, a protein involved in cell adhesion by anchoring the -catenin-E-cadherin complex to the actin cytoskeleton. CTNNA1 has so far only been found mutated in some

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -319- lung, prostate, ovarian, and colon cancer cell lines. Homozygous deletion of CTNNA1 in a human lung cancer cell line lead to loss of cell adhesion, whereas introduction of the wild-type CTNNA1 restored normal adhesion. However, an effect of -catenin inactivation on WNT signaling has not been reported.

PTEN

PTEN is a phosphatase and tensin homologue that by dephosphorylation inhibits the activities of phosphatidylinositol-3 kinase (PI-3K). In PTEN null prostate cancer cell lines, PI-3K activates integrin- linked kinase (ILK), which further phosphorylates and inhibits the activity of GSK-3 . Subsequently, -catenin accumulates in the nucleus and increased expression of the WNT target gene, cyclin D1, is observed. Upon reexpression of wild-type PTEN, GSK-3 activity is elevated, leading to an increase in -catenin phosphorylation and subsequent degradation of -catenin. This might present a key mechanism by which PTEN works as a tumor suppressor protein. Germline mutations in PTEN are associated with Cowden disease. PTEN is also frequently mutated or deleted in a variety of sporadic human malignancies, such as glioblastoma and carcinomas of the prostate, kidney, and breast. In addition, PTEN contains two (A)6 repeats within its coding region and these are found mutated endometrial, colorectal and gastric carcinomas with MSI. Finally, promoter methylation of PTEN has been observed in some solid tumors.

Several novel molecular data have during the last few years contributed to the understanding of the complexity of the WNT signaling pathway. However, many of the underlying mechanisms still remain unknown. Both genetic, epigenetic and expression alterations of molecules in the WNT signaling pathway are characteristic in human solid tumors. In the colorectal adenoma-carcinoma sequence, the majority of the tumors show accumulation of nuclear -catenin and this change is even apparent in aberrant crypt foci. A future perspective, when it comes to anti-cancer therapeutics, would be to block the -catenin-TCF complex and thereby transcription of WNT target genes.

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This paper should be referenced as such : Lin THORSTENSEN, Ragnhild A. LOTHE. The WNT Signaling Pathway and Its Role in Human Solid Tumors.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -331- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Transcription factors

* I Introduction

II Initiation of transcription

III Transcription factors family pdf version

III.1 Helix-Turn-Helix proteins

III.2 Zinc finger proteins

III.3 Leucine zipper proteins

III.4 Helix-Loop-Helix proteins *

I Introduction

In eukaryotic cells, there are three different RNA polymerases (RNA Pol). Each RNA Pol is responsible for a different class of transcription : PolI transcribes rRNA (ribosomal RNA), PolII mRNA (messenger RNA), and PolII tRNA (transfer RNA) and other small RNAs. Any protein that is needed for the initiation of transcription is defined as a transcription factor. Many transciption factors act by recognizing cis- acting sites that are parts of promoters or enhancers. However, binding to DNA is not the only means of action for a transcription factor. A factor may recognize another factor, or may recognize RNA Polymerases. In Eukaryotes, transcription factors, rather than the enzymes themselves, are principally responsible for recognizing the promoter. Transcription factors are able to bind to specific sets of short conserved sequences contained in each promoter. Some of these elements and factors are common, and are found in a variety of promoters and used constitutively; others are specific and their use is regulated. The factors that assists RNA polII can be divided into 3 general groups:

• The general factors, which are required for the initiation of RNA synthesis at all class II promoters (coding genes). With RNA PolII, they form a complex surrounding the transcription startpoint, and they determine the site of initiation ; this complex constitute the basal transcription apparatus.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -332- • The upstream factors, which are DNA-binding proteins that recognize specific short consensus elements located upstream the transcription startpoint (e.g. Sp1, which binds the GC box). These factors are ubiquitous and act upon any promoter that contain the appropriate binding site on DNA. They increase the efficiency of initiation.

• The inducible factors, which function in the same general way as the upstream factors, but have a regulatory role. They are synthesized or activated at specific times and in specific tissues. The sequences that they bind are called response elements.

II Initiation of transcription

RNA pol II enzyme cannot initiate transcription itself, but is absolutely dependent on auxiliary transcription factors (called TFIIX, where "X" is a letter that identifies the individual factor). The enzyme together with these factors constitutes the basal (or minimal) transcriptional apparatus that is needed to transcribe any class II promoter. The efficiency and specificity with which a promoter is recognized depend upon short sequences, farther upstream the TATA box, which are recognized by upstream and inducible factors. Examples of these sequences are the CAAT box, which plays a strong role in determining the efficiency of the promoter, and is recognized in different promoters by different factors, such as factors of the CTF family, the factors CP1 and CP2, and the factors C/EBP and ACF, and the GC box, which is recognized by the factor Sp1. These factors have the ability to interact with one another by protein- protein interactions. The main purpose of the elements is to bring the factors they bind into the vicinity of the initiation complex, where protein-protein interactions determine the efficiency of the initiation reaction.

Figure 1: Schematic model for the assembly of the basal

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -333- transcriptional apparatus

III Transcription factors family

Common types of motifs that are responsible for binding to DNA can be found in different transcription factors. There are several groups of proteins that regulate transcription by using particular motifs to bind DNA :

III.1 Helix-turn-helix proteins

The helix-turn-helix motif was originally identified as the DNA-binding domain of phage repressors; one -helix lies in the wide groove of DNA, the other lies at an angle across DNA. A related form of the motif is present in the homeodomain, a sequence first characterized in several proteins encoded by genes concerned with developmental regulation in Drososphila ; it is also present in genes coding for mammalian transcription factors. The homeobox is a sequence that codes for a domain of 60 amino-acids. The homeodomain is responsible for binding to DNA; the specificity of DNA recognition lies within the homeodomain. Its C-ter region shows homology with the helix-turn-helix motif of procaryotic repressors.

III.2 Zinc finger proteins

The zinc-finger motif comprises a DNA-binding domain. It was originally found in the factor TFIIIA, which is required for RNA PoIIII to transcribe 5S rRNA genes. These proteins take their name from their structure, in which a small group of conserved aminoacids binds a zinc ion. Two types of DNA-binding proteins have structures of this type: the classic " zinc finger " proteins, and the steroid receptors. A " finger protein " typically has a series of zinc fingers; the consensus sequence of a single finger is: Cys-X2-4-Cys-X3-Phe-X3-Leu-X2-His-X3-His The motif takes its name from the loop of aminoacids that protrudes from the zinc- binding site and is described as the Cys2/His2 finger. The fingers are usually organized as a single series of tandem repeats ; the stretch of fingers ranges from 9 repeats that occupy almost the entire protein (as in TFIIIA), to providing just one small domain consisting on 2 fingers ; the general transcription factor Sp1 has a DNA-binding domain that consists of 3 zinc fingers. The C-terminal part of each finger forms -helices that bind DNA ; the N-terminal part form -sheets. The non-conseved aminoacids in the C-terminal side of each finger are responsible for recognizing specific target sites. Steroid receptors, which are activated by binding a particular steroid (e.g. glucocorticoids, thyroid hormone, retinoic acid), and some other proteins, have another type of finger. The structure is based on a sequence with the zinc-binding consensus :

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -334- Cys-X2-Cys-X13-Cys-X2-Cys These are called Cys2/Cys2 fingers. Proteins with Cys2/Cys2 fingers often have non- repetitive fingers, in contrast with the tandem repetition of the Cys2/His2 type. Binding sites on DNA are usually short and palindromic. The glucocorticoid and estrogen receptors each have 2 fingers, that form -helices that fold together to form a large globular domain.

III. 3 Leucine zipper proteins

The leucine zipper is a stretch of aminoacids rich in leucine residues that provide a dimerization motif. Dimerization allows the juxtaposition of the DNA-binding regions of each subunit. A leucine zipper forms an amphipathic helix in which the leucines of the zipper on one protein could protrude from the -helix and interdigitate with the leucines of the zipper of another protein in parallel to form a coiled coil domain. The region adjacent to the leucine repeats is highly basic in each of the zipper proteins, and could comprise a DNA-binding site. The 2 leucine zippers in effect form a Y- shaped structure, in which the zippers comprise the stem, and the 2 basic regions bifurcate simmetrically to form the arms that bind to DNA. This is known as the bZIP structural motif. It explains why the target sequences for such proteins are inverted repeats with no separation. Zippers may be used to sponsor the formation of homodimers or heterodimers. There are 4 repeats in the protein C/EBP (a factor that binds as a dimer to both the CAAT box and the SV40 core enhancer), and 5 repeats in the factors and (which form the heterodimeric transcription factor AP1).

III.4 Helix-loop-helix proteins

The amphipathic helix-loop-helix (HLH) motif has been identified in some developmental regulators and in genes coding for eukaryotic DNA-binding proteins. The proteins that have this motif have both the ability to bind DNA and to dimerize. They share a common type of sequence motif: a stretch of 40-50 aminoacids contains 2 amphipathic -helices separated by a linker region (the loop) of varying length. The proteins in this group form both homodimers and heterodimers by means of interactions between the hydrophobic residues on the corresponding faces of the 2 helices. The ability to form dimers resides with these amphipathic helices, and is common to all HLH proteins. Most HLH proteins contain a region adjacent to the HLH motif itself that is highly basic, and which is needed for binding to DNA. Members of the group with such a region are called bHLH proteins. A dimer in which both subunits have the basic region can bind to DNA. The bHLH proteins fall into 2 general groups. Class A consists of proteins that are ubiquitously expressed, including mammalian E12/E47. Class B consists of proteins that are expressed in a tissue-specific manner, including mammalian MyoD, Myf5, myogenin and MRF4 (a group of transcription factors that are involved in myogenesis, called myogenic regulatory factors, MRFs). A common modus operandi for a tissue-specific bHLH protein may be to form a heterodimer with a ubiquitous partner. There is also a group of gene products that specify development of the nervous system in Drosophila melanogaster (where Ac-S is the tissue-specific component, and da is the ubiquitous component). The proteins form a separate class of bHLH proteins.

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -335-

Contributor(s) Written 04- Valentina Guasconi, Hakima Yahi, Slimane Ait-Si-Ali 2003

Citation This paper should be referenced as such : Guasconi V, Yahi H, Ait-Si-Ali S . Transcription factors. Atlas Genet Cytogenet Oncol Haematol. April 2003 . URL : http://www.infobiogen.fr/services/chromcancer/ Educ/TFactorsEng

Atlas Genet Cytogenet Oncol Haematol 2003; 2 -336-