Volume 1 - Number 1 May - September 1997
Volume 19 - Number 8 August 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematologyis a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university (university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using information technology, between the increasing amount of knowledge and the individual, having to use the information. Towards a personalized medicine of cancer.
It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.
See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf
Editorial correspondance
Jean-Loup Huret, MD, PhD, Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France phone +33 5 49 44 45 46 [email protected] or [email protected] .
Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) Staff: Vanessa Le Berre Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).
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The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS Editor-in-Chief Jean-Loup Huret (Poitiers, France)
Board Members SreeparnaBanerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected] Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; Antonio Cuneo [email protected] Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Paola Dal Cin [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des François Desangles Irradiations, Dewoitine C212, 91223 Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Enric Domingo Oxford, OX37BN, UK [email protected] AyseElifErson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Kessel Sciences, 6500 HB Nijmegen, The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Oskar A. Haas Children's Cancer Research Institute Vienna, Vienna, Austria. [email protected] Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; Anne Hagemeijer [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, NylaHeerema USA; [email protected] Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; SakariKnuutila [email protected] Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; Lidia Larizza l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell RoderickMcLeod Cultures, Braunschweig, Germany; [email protected] Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; Cristina Mecucci [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Fredrik Mertens Sweden; [email protected] Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; miller.konstantin@mh- Konstantin Miller hannover.de Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Felix Mitelman Sweden; [email protected] HossainMossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Stefan Nagel Cultures, Braunschweig, Germany; [email protected] Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; Florence Pedeutour [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Susana Raimondi Memphis, Tennessee 38105-3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; Sabine Strehl [email protected] Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; Nancy Uhrhammer [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato Roberta Vanni (CA) - Italy; [email protected] Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Franck Viguié Universitaire Necker-Enfants Malades, 75015 Paris, France; [email protected]
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’InformationScientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Volume 19, Number 8, August 2015 Table of contents
Gene Section
ADAM23 (ADAM metallopeptidase domain 23) 491 Erico T Costa, Anamaria A Camargo ADCYAP1 (adenylate cyclase activating polypeptide 1 (pituitary)) 495 Terry Moody ERGIC3 (ERGIC and golgi 3) 499 Mingsong Wu, Yi Cao NFE2L2 (nuclear factor, erythroid 2-like 2) 503 Stavroula D Manolakou, Panos G Ziros, Gerasimos P Sykiotis NR5A1 (nuclear receptor subfamily 5, group A, member 1) 522 Carmen Ruggiero, Mabrouka Doghman, Enzo Lalli SGK1 (serum/glucocorticoid regulated kinase 1) 535 Miranda Menniti, Rodolfo Iuliano, Lucia D'Antona, Cristina Talarico, Rosario Amato, Nicola Perrotti
Leukaemia Section t(14;17)(q32;q21) IGH/IGF2BP1 541 Guangyu Gu, Sarah South t(5;12)(q33;p13) ATF7IP/PDGFRB 543 Kenichiro Kobayashi
Solid Tumour Section
Lung: Translocations in Squamous Cell Carcinoma 545 Jean-Loup Huret
Atlas Genet Cytogenet Oncol Haematol. 1998; 2(1) Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Review
ADAM23 (ADAM metallopeptidase domain 23) Erico T Costa, Anamaria A Camargo Ludwig Institute for Cancer Research - at Hospital Sirio-Libanes, Sao Paulo - SP - Brazil (ETC, AAC)
Published in Atlas Database: September 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/ADAM23ID44041ch2q33.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62256/09-2014-ADAM23ID44041ch2q33.pdf DOI: 10.4267/2042/62256 This article is an update of : Calmon MF, Rahal P. ADAM23 (ADAM metallopeptidase domain 23). Atlas Genet Cytogenet Oncol Haematol 2008;12(1)
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
and probably plays its biological role through the Abstract disintegrin domain. ADAM23 is involved in cell-cell ADAM23 belongs to the ADAM (A Disintegrin And adhesion and communication and cell-matrix Metalloproteinase domain) family of proteins. modulation. Members of this family present a common structural The ADAM23 gene is frequently silenced by DNA organization including metalloprotease, disintegrin, promoter methylation in different types of solid cystein-rich, epidermal growth factor-like, cancers and epigenetic inactivation is associated transmembrane and cytoplasmatic domains and are with cancer progression, increased tumor cell structurally related to snake venom disintegrins. mobility and reduced tumor cell proliferation. ADAM23 has close similarity to ADAM11 and Keywords ADAM22; is highly expressed in the CNS, and is ADAM family, cell-cell adhesion, cell migration, crucial for normal brain development. Mice invasion, proliferation, differentiation, metastasis homozygous for an insertional mutation that inactivates the gene are smaller than normal Identity littermates, show delayed lung development, are Other names: MDC3 lethal by postnatal day 14, and display severe tremor and ataxia. HGNC (Hugo): ADAM23 ADAM23 does not present metalloprotease activity Location: 2q33.3
Genomic structure of ADAM23 human gene composed of 27 coding exons. Black boxes represent constitutive exons present in all splicing isoforms. Colored boxes represent alternatively spliced exons.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 491 ADAM23 (ADAM metallopeptidase domain 23) Costa ET, Camargo AA
Domain structure of ADAM23. Its deduced amino acid sequence lacks essential residues conserved in metalloproteinases (adapted from Cal et al., 2000).
Size: 832 amino acid; 92 kDa predicted (RefSeq DNA/RNA NP_003803). Description Expression DNA contains 177488 bp composed of 27 coding Detected at medium/high expression levels in 46 of exons (26 reported by RefSeq sequences). 82 analyzed normal tissue types, including: brain, testis, lung, breast, colon, pancreas and kidney Transcription (according to The Human Protein Atlas). 6236 bp mRNA transcribed (RefSeq NM_003812.3) Localisation in centromeric to telomeric orientation; 2499 bp open reading frame. There are three alternative Cell membrane; single-pass type I membrane protein splicing isoforms of the human ADAM23 gene: (isoform ADAM23-alpha and ADAM23-beta). ADAM23-alpha (chosen as the 'canonical' Secreted protein (predicted for ADAM23-gama sequence), ADAM23-beta and ADAM23-gamma. isoform). These splicing isoforms are generated by the Function mutually exclusive use or skipping of the exons 25 ADAM23 was originally described to promote and/or 26, both of which coding for transmembrane neuroblastoma and astrocytoma cell-cell adhesion domains with different aminoacid compositions. The via direct interaction with alphavbeta3 integrin. ADAM23 proteins encoded by the alpha and beta Following reports showed that the interaction splicing isoforms are anchored to the membrane by between ADAM23 and alphavbeta3 integrin inhibits different transmembrane domains (encoded by exon cell-matrix adhesion and negatively modulates 26 in the isoform alpha and by exon 25 in the isoform alphavbeta3 activation during metastatic beta) and are predicted to have distinct membrane progression. Silencing of the ADAM23 gene subdomain localizations. ADAM23-gamma is promotes cell cycle arrest and terminal generated by exon skipping of exons 25 and 26 and differentiation in P19 mice embryonic carcinoma therefore lacks the transmembrane domain and is cells and, in MDA-MB435 and SK-Mel37 tumor cell predicted to be either a cytoplasmatic or a secreted lines, promotes tumor cell migration and invasion isoform of the ADAM23 protein. ADAM23 mRNA and inhibits tumor cell proliferation. is detected at high or medium expression levels in brain, testis and heart muscle (The Human Protein Homology Atlas, ENSG00000114948). H. sapiens: ADAM23, P. troglodytes: ADAM23, C. Pseudogene lupus: LOC607871, M. musculus: ADAM23, R. novergicus: ADAM23, G. gallus: LOC424099. No pseudogenes reported. Mutations Protein Note Description No mutations have been reported for ADAM23 ADAM23 is a non-catalytically active member of gene. ADAM family and exhibits all the conserved protein Germinal domains, including: an N-terminal signal, a pro- domain, a metalloprotease and a disintegrin No germline mutations have been reported for the domains, a cysteine-rich region, an EGF-like ADAM23 gene (OMIM603710). domain, a transmembrane and a short cytoplasmic Somatic domains. Within the metalloprotease domain, No somatic point mutations and CNVs have been ADAM23 lacks the conserved zinc-binding reported. sequence HEXXHXXGXXH, which is critical for the proteinase activity. Interacts with LGI1, LGI3 Epigenetics and LGI4 (leucine-rich glioma inactivated family), Epigenetic silencing of the ADAM23 have been alphav-beta3 integrins and PrPc proteins. frequently reported in different types of solid tumors.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 492
ADAM23 (ADAM metallopeptidase domain 23) Costa ET, Camargo AA
Immunohistochemistry staining of ADAM23 protein in normal colon and normal breast tissues was carried out using the polyclonal antibody anti-ADAM23 (HPA012130, Sigma) (photograph courtesy of Dra. Gabriela F Barnabe from Ludwig Institute for Cancer Research - SP - Brazil).
Implicated in Gastric tumors ADAM23 promoter hypermethylation is frequently Breast carcinoma observed in gastric dysplasia (90%) and gastric ADAM23 expression is downregulated by promoter tumors (29-55%) but is rarely observed in normal hypermethylation during breast cancer progression mucosa (9%). The frequency of ADAM23 and hypermethylation was significantly associated methylation is higher in metastatic lesions compared with a higher incidence of distant metastasis and to paired primary tumors. Homozygous loss of reduced overall survival. Recently, ADAM23 ADAM23 was also reported for gastric tumors but at epigenetic silencing during tumor progression was a lower frequency (~3%). shown to generate genetic and functional heterogeneity in invasive breast tumors. ADAM23- Pancreatic tumors intratumoral heterogeneity (ADAM23-ITH) was ADAM23 promoter methylation was detected in 7 observed in topographically distinct areas of out of 24 (29%) primary invasive pancreatic ductal undifferentiated breast invasive ductal carcinomas, adenocarcinomas. with invasive components being frequently composed by mosaic clusters of ADAM23-positive Head and neck cancer tumor cells coexisting in close proximity with ADAM23 promoter hypermethylation was detected ADAM23-silenced cells. Most importantly, it was in 18 out of 43 head and neck tumors (42%) and a demonstrated that ADAM23-ITH promotes tumor significant association between ADAM23 growth and metastasis by establishing a crosstalk hypermethylation and advanced stages (T3-T4) was between ADAM23-positives and ADAM23- observed larynx tumors. negatives tumor cells in which ADAM23-negative Multiple myeloma cells promote tumor growth and metastasis by enhancing the proliferation and invasion of adjacent ADAM23 mRNA expression is absent in normal ADAM23-positive cells through the production of bone marrow plasma cells, but is aberrantly the ADAM23-ligant LGI4 (leucine-rich glioma expressed in 2/131 (1,5%) patients with newly Inactivated gene 4) and pro-migratory levels of nitric diagnosed multiple myeloma. In two independent oxide (NO). cohorts of patients with primary multiple myeloma, Lung carcinoma 24 out of 557 patients (4%) showed increased levels of ADAM23 mRNA expression, which was ADAM23 protein levels is lower in non-small-cell significantly associated with poor overall survival. lung carcinoma (NSCLC) compared to corresponding normal tissues and benign pulmonary References lesions, and a decrease in ADAM23 protein expression was observed during NSCLC Sagane K, Ohya Y, Hasegawa Y, Tanaka I. Metalloproteinase-like, disintegrin-like, cysteine-rich progression. Hypermethylation of ADAM23 proteins MDC2 and MDC3: novel human cellular promoter region was observed in 40% of NSCLC but disintegrins highly expressed in the brain. Biochem J. 1998 in only 7.6% of the adjacent normal tissues. Aug 15;334 ( Pt 1):93-8
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ADAM23 (ADAM metallopeptidase domain 23) Costa ET, Camargo AA
Poindexter K, Nelson N, DuBose RF, Black RA, Cerretti DP. metastatic gastric carcinoma. Oncol Rep. 2009 The identification of seven metalloproteinase-disintegrin May;21(5):1251-9 (ADAM) genes from genomic libraries. Gene. 1999 Sep 3;237(1):61-70 Watanabe Y, Kim HS, Castoro RJ, Chung W, Estecio MR, Kondo K, Guo Y, Ahmed SS, Toyota M, Itoh F, Suk KT, Cho Cal S, Freije JM, López JM, Takada Y, López-Otín C. ADAM MY, Shen L, Jelinek J, Issa JP. Sensitive and specific 23/MDC3, a human disintegrin that promotes cell adhesion detection of early gastric cancer with DNA methylation via interaction with the alphavbeta3 integrin through an analysis of gastric washes. Gastroenterology. 2009 RGD-independent mechanism. Mol Biol Cell. 2000 Jun;136(7):2149-58 Apr;11(4):1457-69 Bret C, Hose D, Reme T, Kassambara A, Seckinger A, Costa FF, Verbisck NV, Salim AC, Ierardi DF, Pires LC, Meissner T, Schved JF, Kanouni T, Goldschmidt H, Klein B. Sasahara RM, Sogayar MC, Zanata SM, Mackay A, O'Hare Gene expression profile of ADAMs and ADAMTSs M, Soares F, Simpson AJ, Camargo AA. Epigenetic metalloproteinases in normal and malignant plasma cells silencing of the adhesion molecule ADAM23 is highly and in the bone marrow environment. Exp Hematol. 2011 frequent in breast tumors. Oncogene. 2004 Feb May;39(5):546-557.e8 19;23(7):1481-8 Hu C, Lv H, Pan G, Cao H, Deng Z, Hu C, Wen J, Zhou J. Hagihara A, Miyamoto K, Furuta J, Hiraoka N, Wakazono K, The expression of ADAM23 and its correlation with Seki S, Fukushima S, Tsao MS, Sugimura T, Ushijima T. promoter methylation in non-small-cell lung carcinoma. Int J Identification of 27 5' CpG islands aberrantly methylated Exp Pathol. 2011 Oct;92(5):333-9 and 13 genes silenced in human pancreatic cancers. Oncogene. 2004 Nov 11;23(53):8705-10 Wang Y, Sun Y, Qiao S. ADAM23 knockdown promotes neuronal differentiation of P19 embryonal carcinoma cells Sun YP, Deng KJ, Wang F, Zhang J, Huang X, Qiao S, Zhao by up-regulating P27KIP1 expression. Cell Biol Int. S. Two novel isoforms of Adam23 expressed in the 2012;36(12):1275-9 developmental process of mouse and human brains. Gene. 2004 Jan 21;325:171-8 Starlard-Davenport A, Kutanzi K, Tryndyak V, Word B, Lyn- Cook B. Restoration of the methylation status of Takada H, Imoto I, Tsuda H, Nakanishi Y, Ichikura T, hypermethylated gene promoters by microRNA-29b in Mochizuki H, Mitsufuji S, Hosoda F, Hirohashi S, Ohki M, human breast cancer: A novel epigenetic therapeutic Inazawa J. ADAM23, a possible tumor suppressor gene, is approach. J Carcinog. 2013;12:15 frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation. Oncogene. Costa ET, Barnabé GF, Li M, Dias AA, Machado TR, 2005 Dec 1;24(54):8051-60 Asprino PF, Cavalher FP, Ferreira EN, Del Mar Inda M, Nagai MH, Malnic B, Duarte ML, Leite KR, de Barros AC, Calmon MF, Colombo J, Carvalho F, Souza FP, Filho JF, Carraro DM, Chammas R, Armelin HA, Cavenee W, Furnari Fukuyama EE, Camargo AA, Caballero OL, Tajara EH, F, Camargo AA. Intratumoral heterogeneity of ADAM23 Cordeiro JA, Rahal P. Methylation profile of genes CDKN2A promotes tumor growth and metastasis through LGI4 and (p14 and p16), DAPK1, CDH1, and ADAM23 in head and nitric oxide signals. Oncogene. 2014 Mar 24;0 neck cancer. Cancer Genet Cytogenet. 2007 Feb;173(1):31-7 This article should be referenced as such: Sun Y, Wang Y, Zhang J, Tao J, Wang C, Jing N, Wu C, Costa ET, Camargo AA. ADAM23 (ADAM Deng K, Qiao S. ADAM23 plays multiple roles in neuronal metallopeptidase domain 23). Atlas Genet Cytogenet differentiation of P19 embryonal carcinoma cells. Oncol Haematol. 2015; 19(8):491-494. Neurochem Res. 2007 Jul;32(7):1217-23 Kim JH, Jung EJ, Lee HS, Kim MA, Kim WH. Comparative analysis of DNA methylation between primary and
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 494 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Review
ADCYAP1 (adenylate cyclase activating polypeptide 1 (pituitary)) Terry Moody National Cancer Institute, Center for Cancer Research, Office of the Director, 9609 Medical Center Drive, Rm 2W130, Bethesda, Maryland 20892, USA (TM)
Published in Atlas Database: September 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/ADCYAP1ID43656ch18p11.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62257/09-2014-ADCYAP1ID43656ch18p11.pdf DOI: 10.4267/2042/62257 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Transcription Review on ADCYAP1, with data on DNA/RNA, on The gene transcript is 2.7 kb (Ghatei et al., 1993). the protein encoded and where the gene is implicated. Protein Note Identity Pituitary adenylate cyclase-activating polypeptide Other names: PACAP (PACAP) was isolated from ovine hypothalamus and contains 38 amino acids. HGNC (Hugo): ADCYAP1 PACAP-38 elevates cAMP in rat pituitary cells in Location: 18p11.32 culture (Miyata et al., 1989). Local order: PACAP-27 was isolated from ovine hypothalamus The PACAP gene has 5 exons. and had the same N-terminal 27 amino acids as does PACAP-38 (Miyata et al., 1990). Note: PACAP-27 or PACAP-38 are secreted PACAP-27 has high homology with vasoactive proteins which binds to membrane G-protein intestinal peptide (VIP) and moderate homology coupled receptors (GPCR) increasing intracellular with PRP. cAMP signaling. The PACAP-38 amino acid sequence is identical in mammals. DNA/RNA PACAP has a β-turn at residues 9-12, followed by an Note α-helix at residues 12-14, 15-20 and 22-24 (Inooka The ADCYAP1 gene encodes 5 exons and is et al., 1992). PACAP binds with high affinity to 3 localized to chromosome 18p11 (Kimura et al., GPCR (VPAC1, VPAC2 and PAC1) which are 1990). Exons 1 and 2 encode for the 5'UTR and the members of the class II or class B secretin-like signal peptide. Exon 3 encodes for the N-terminal of receptors (Harmar et al., 2012). pro-PACAP upstream from PRP. PRP is encoded by The activated VPAC1, VPAC2 or PAC1 interacts Exon 4. Exon 5 encodes for the C-terminal of pro- with a stimulatory guanine nucleotide binding PACAP including PACAP-27, PACAP-38 and the protein (Gs) increasing adenylylcyclase activity 3'UTR (Vaudry et al., 2009). resulting in elevated cAMP (Arimura et al., 1992). The increased cAMP activates protein kinase (PK) A Description causing phosphorylation of various proteins such as The PACAP gene which contains 7230 bases is CREB leading to altered gene expression (Moody et highly conserved in nature (Sherwood et al., 2000). al., 2003).
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 495 ADCYAP1 (adenylate cyclase activating polypeptide 1 Moody T (pituitary))
Structure of human prepro-PACAP. Human prepro-PACAP (1-176) is metabolized by signal proteases to generate pro-PACAP (26-176). Pro-PACAP is metabolized by pro-hormone convertases to (26-79), big PACAP-related peptide (82-129; PRP) and PACAP-38. Pro-PACAP (26-176) can be further metabolized to PRP (82-109) and PACAP-27 by other enzymes. PACAP is derived from the 176 amino acid precursor protein prepro-PACAP. Initially the signal peptide (1-25) is cleaved by signal proteases to generate pro-PACAP (26-176). Pro-PACAP is metabolized by pro-hormone convertases and carboxypeptidases to (26-79), (82-129) and (132-170). The C-terminal peptides (132-170) and (132-159) are metabolized to by peptidylglycine alpha-amidating monooxygenase enzymes to PACAP-38 and PACAP-27, respectively, which have amidated C- terminals.
In addition, PAC1 interacts with Gq causing Homology phosphatidylinositol (PI) turnover (Pisegna and Wank, 1996). The resulting metabolites inositol- VIP has 67% sequence homology with PACAP-27. 1,4,5-trisphosphate and diacylglycerol increases The sequence for PACAP-38 is identical in cytosolic calcium and activates protein kinase C, mammals (Fahrenkrug, 2010). respectively. Mutations Expression PACAP is produced in neurons within the adrenals, Note brain, gastrointestinal (GI) tract, pituitary and testis Sequence mutations of PACAP-38 are rare. (Ghatei et al., 1993). Addition of PACAP to adrenal Numerous mutations of PAC1 have been reported chormaffin cells causes catecholamine release including deletions, which affect PACAP binding (Watanabe et al., 1990). High densities of PACAP (PAC1 short; PAC1 very short) and splice variants, are present in the hypothalamus and PACAP as well which affect signal transduction (hip, hop1, hop2; as glutamate shift the circadian rhythm in the Blechman and Levkowitz, 2013). SNP rs2267735 of suprachiasmatic nucleus (Vaudry et al., 2009). In the PAC1 is associated with post-traumatic stress gastrointestinal tract PACAP stimulates the disorder (PTSD) in females (Ressler et al., 2011). secretion of saliva, gastric acid, bicarbonate and peptides leading to myorelaxation (Moody et al., Implicated in 2011). In PACAP knockout mice or mice treated with PACAP(6-38) there is reduced insulin secretion Lung cancer after glucose challenge (Shintani et al., 2003). In PACAP-38 immunoreactivity is higher in the human pituitary cells, PACAP elevates cAMP increasing lung cancer than normal lung biopsy specimens the secretion of LH, GH, PRL, ACTH and TSH (Szanto et al., 2012). PAC1 is present in lung cancer (Vaudry et al., 2009). The results indicate that cells and PACAP(6-38) inhibits their proliferation PACAP is present in the normal CNS and periphery. (Zia et al., 1995). PACAP-27 may stimulate lung cancer proliferation as a result of EGFR Localisation transactivation (Moody et al., 2012). Prepro-PACAP is stored in dense core neurosecretory granules in cells. In cellular extracts Breast cancer approximately an order of magnitude more PACAP- A 19.9 kDa prepro-PACAP was detected in human 38 is detected than PRP or PACAP-27. PACAP-38 breast cancer biopsy specimens (Garcia Fernandez et and PACAP-27 have approximately an order of al., 2004). PACAP-27 stimulated and PACAP(6-38) magnitude more biological activity than does PRP inhibited the growth of breast cancer cells (Leyton et (Fahrenkrug, 2010). PACAP is metabolized by al., 1999). neutral endopeptidase and has a half life of 5 min. Colon cancer Function PACAP knockout mice but not wild type mice PACAP alters neurotransmitter release in the CNS, develop colitis and colorectal tumors after treatment causes increased insulin and histamine secretion in with dextran sulfate sodium (Nemetz et al., 2008). the periphery, controls vasodilation, bronchodilation PACAP-38 stimulates the growth of colon cancer alters intestinal motility and stimulates cellular cells (Le et al., 2002). proliferation as well as differentiation (Vaudry et al., 2009).
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 496
ADCYAP1 (adenylate cyclase activating polypeptide 1 Moody T (pituitary))
Pheochromocytoma Watanabe T, Ohtaki T, Kitada C, Tsuda M, Fujino M. Adrenal pheochromocytoma PC12h cells respond to PACAP increases the cAMP after addition to PC12 pituitary adenylate cyclase activating polypeptide. Biochem adrenal pheochromocytoma cells (Watanabe et al., Biophys Res Commun. 1990 Nov 30;173(1):252-8 1990) and causes catecholamine secretion (Taupenot Arimura A. Pituitary adenylate cyclase activating et al., 1999). PACAP addition to PC12 cells polypeptide (PACAP): discovery and current status of increases their survival as a result of Trk receptor research. Regul Pept. 1992 Feb 18;37(3):287-303 tyrosine kinase phosphorylation and activation of Inooka H, Endo S, Kitada C, Mizuta E, Fujino M. Pituitary Akt (Rajagopal et al., 2004). adenylate cyclase activating polypeptide (PACAP) with 27 residues. Conformation determined by 1H NMR and CD Pituitary adenoma spectroscopies and distance geometry in 25% methanol solution. Int J Pept Protein Res. 1992 Nov;40(5):456-64 PACAP inhibits apoptosis caused by TGFβ addition to human pituitary adenoma cells (Oka et al., 1999). Ghatei MA, Takahashi K, Suzuki Y, Gardiner J, Jones PM, PAC1 receptor mRNA was present in all pituitary Bloom SR. Distribution, molecular characterization of pituitary adenylate cyclase-activating polypeptide and its adenoma cells except prolactnomas (Oka et al., precursor encoding messenger RNA in human and rat 1998). tissues. J Endocrinol. 1993 Jan;136(1):159-66 Medulloblastoma Zia F, Fagarasan M, Bitar K, Coy DH, Pisegna JR, Wank SA, Moody TW. Pituitary adenylate cyclase activating Disruption of a single copy of the PACAP gene peptide receptors regulate the growth of non-small cell lung increased medulloblastoma incidence in ptc1 mutant cancer cells. Cancer Res. 1995 Nov 1;55(21):4886-91 mice 2.5-fold (Lelievre et al., 2008). Canonico PL, Copani A, D'Agata V, Musco S, Petralia S, Diabetes Travali S, Stivala F, Cavallaro S. Activation of pituitary adenylate cyclase-activating polypeptide receptors ADCYAP1 stimulates insulin secretion in a glucose- prevents apoptotic cell death in cultured cerebellar granule dependent manner (Filipsson et al., 2001). Two cells. Ann N Y Acad Sci. 1996 Dec 26;805:470-2 SNPs g.9863G>A, G54D in exon 3, and Pisegna JR, Wank SA. Cloning and characterization of the g.12712C>G in exon 5 were found in European type signal transduction of four splice variants of the human 2 diabetic patients (Gu et al., 2002). pituitary adenylate cyclase activating polypeptide receptor. Evidence for dual coupling to adenylate cyclase and Neuronal survival phospholipase C. J Biol Chem. 1996 Jul 19;271(29):17267- 74 PACAP stimulates neurite outgrowth and enhances neuronal cell survival (Canonico et al., 1996). Oka H, Jin L, Reubi JC, Qian X, Scheithauer BW, Fujii K, Kameya T, Lloyd RV. Pituitary adenylate-cyclase-activating PACAP addition to rat cerebellar neurites increases polypeptide (PACAP) binding sites and PACAP/vasoactive cAMP and inhibits caspase-3 activity (Vaudry et al., intestinal polypeptide receptor expression in human 2009). pituitary adenomas. Am J Pathol. 1998 Dec;153(6):1787-96 Schizophrenia Leyton J, Gozes Y, Pisegna J, Coy D, Purdom S, Casibang M, Zia F, Moody TW. PACAP(6-38) is a PACAP receptor In PACAP knockout mice and schizophrenic antagonist for breast cancer cells. Breast Cancer Res Treat. patients, brain strathmin I is up-regulated 1999 Jul;56(2):177-86 (Hashimoto et al., 2007). PACAP reduces Strathmin Oka H, Jin L, Kulig E, Scheithauer BW, Lloyd RV. Pituitary I in animal models of schizophrenia by inhibiting the adenylate cyclase-activating polypeptide inhibits association of the DISCI-binding zinc-finger protein transforming growth factor-beta1-induced apoptosis in a with DBZ (Katayama et al., 2009). human pituitary adenoma cell line. Am J Pathol. 1999 Dec;155(6):1893-900 Taupenot L, Mahata M, Mahata SK, O'Connor DT. Time- References dependent effects of the neuropeptide PACAP on Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, catecholamine secretion : stimulation and desensitization. Jiang L, Culler MD, Coy DH. Isolation of a novel 38 residue- Hypertension. 1999 Nov;34(5):1152-62 hypothalamic polypeptide which stimulates adenylate Sherwood NM, Krueckl SL, McRory JE. The origin and cyclase in pituitary cells. Biochem Biophys Res Commun. function of the pituitary adenylate cyclase-activating 1989 Oct 16;164(1):567-74 polypeptide (PACAP)/glucagon superfamily. Endocr Rev. Kimura C, Ohkubo S, Ogi K, Hosoya M, Itoh Y, Onda H, 2000 Dec;21(6):619-70 Miyata A, Jiang L, Dahl RR, Stibbs HH. A novel peptide Filipsson K, Kvist-Reimer M, Ahrén B. The neuropeptide which stimulates adenylate cyclase: molecular cloning and pituitary adenylate cyclase-activating polypeptide and islet characterization of the ovine and human cDNAs. Biochem function. Diabetes. 2001 Sep;50(9):1959-69 Biophys Res Commun. 1990 Jan 15;166(1):81-9 Gu HF. Genetic variation screening and association studies Miyata A, Jiang L, Dahl RD, Kitada C, Kubo K, Fujino M, of the adenylate cyclase activating polypeptide 1 Minamino N, Arimura A. Isolation of a neuropeptide (ADCYAP1) gene in patients with type 2 diabetes. Hum corresponding to the N-terminal 27 residues of the pituitary Mutat. 2002 May;19(5):572-3 adenylate cyclase activating polypeptide with 38 residues (PACAP38). Biochem Biophys Res Commun. 1990 Jul Le SV, Yamaguchi DJ, McArdle CA, Tachiki K, Pisegna JR, 31;170(2):643-8 Germano P. PAC1 and PACAP expression, signaling, and
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ADCYAP1 (adenylate cyclase activating polypeptide 1 Moody T (pituitary))
effect on the growth of HCT8, human colonic tumor cells. Vaudry H. Pituitary adenylate cyclase-activating Regul Pept. 2002 Nov 15;109(1-3):115-25 polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev. 2009 Sep;61(3):283-357 Moody TW, Chan D, Fahrenkrug J, Jensen RT. Neuropeptides as autocrine growth factors in cancer cells. Fahrenkrug J. VIP and PACAP. Results Probl Cell Differ. Curr Pharm Des. 2003;9(6):495-509 2010;50:221-34 Shintani N, Tomimoto S, Hashimoto H, Kawaguchi C, Baba Moody TW, Ito T, Osefo N, Jensen RT. VIP and PACAP: A. Functional roles of the neuropeptide PACAP in brain and recent insights into their functions/roles in physiology and pancreas. Life Sci. 2003 Dec 5;74(2-3):337-43 disease from molecular and genetic studies. Curr Opin Endocrinol Diabetes Obes. 2011 Feb;18(1):61-7 García-Fernández MO, Bodega G, Ruíz-Villaespesa A, Cortés J, Prieto JC, Carmena MJ. PACAP expression and Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, distribution in human breast cancer and healthy tissue. Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Cancer Lett. 2004 Mar 18;205(2):189-95 Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V. Post-traumatic stress disorder is Rajagopal R, Chen ZY, Lee FS, Chao MV. Transactivation associated with PACAP and the PAC1 receptor. Nature. of Trk neurotrophin receptors by G-protein-coupled receptor 2011 Feb 24;470(7335):492-7 ligands occurs on intracellular membranes. J Neurosci. 2004 Jul 28;24(30):6650-8 Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI. Hashimoto R, Hashimoto H, Shintani N, Chiba S, Hattori S, Pharmacology and functions of receptors for vasoactive Okada T, Nakajima M, Tanaka K, Kawagishi N, Nemoto K, intestinal peptide and pituitary adenylate cyclase-activating Mori T, Ohnishi T, Noguchi H, Hori H, Suzuki T, Iwata N, polypeptide: IUPHAR review 1. Br J Pharmacol. 2012 Ozaki N, Nakabayashi T, Saitoh O, Kosuga A, Tatsumi M, May;166(1):4-17 Kamijima K, Weinberger DR, Kunugi H, Baba A. Pituitary adenylate cyclase-activating polypeptide is associated with Moody TW, Osefo N, Nuche-Berenguer B, Ridnour L, Wink schizophrenia. Mol Psychiatry. 2007 Nov;12(11):1026-32 D, Jensen RT. Pituitary adenylate cyclase-activating polypeptide causes tyrosine phosphorylation of the Lelievre V, Seksenyan A, Nobuta H, Yong WH, Chhith S, epidermal growth factor receptor in lung cancer cells. J Niewiadomski P, Cohen JR, Dong H, Flores A, Liau LM, Pharmacol Exp Ther. 2012 Jun;341(3):873-81 Kornblum HI, Scott MP, Waschek JA. Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant Szanto Z, Sarszegi Z, Reglodi D, Nemeth J, Szabadfi K, mice. Dev Biol. 2008 Jan 1;313(1):359-70 Kiss P, Varga A, Banki E, Csanaky K, Gaszner B, Pinter O, Szalai Z, Tamas A. PACAP immunoreactivity in human Nemetz N, Abad C, Lawson G, Nobuta H, Chhith S, Duong malignant tumor samples and cardiac diseases. J Mol L, Tse G, Braun J, Waschek JA. Induction of colitis and rapid Neurosci. 2012 Nov;48(3):667-73 development of colorectal tumors in mice deficient in the neuropeptide PACAP. Int J Cancer. 2008 Apr Blechman J, Levkowitz G. Alternative Splicing of the 15;122(8):1803-9 Pituitary Adenylate Cyclase-Activating Polypeptide Receptor PAC1: Mechanisms of Fine Tuning of Brain Katayama T, Hattori T, Yamada K, Matsuzaki S, Tohyama Activity. Front Endocrinol (Lausanne). 2013;4:55 M. Role of the PACAP-PAC1-DISC1 and PACAP-PAC1- stathmin1 systems in schizophrenia and bipolar disorder: This article should be referenced as such: novel treatment mechanisms? Pharmacogenomics. 2009 Dec;10(12):1967-78 Moody T. ADCYAP1 (adenylate cyclase activating polypeptide 1 (pituitary)). Atlas Genet Cytogenet Oncol Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Haematol. 2015; 19(8):495-498. Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L,
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Gene Section Short Communication
ERGIC3 (ERGIC and golgi 3) Mingsong Wu, Yi Cao Department of Cell Biology and Genetics, Zunyi Medical University, Guizhou Zunyi 563000, China (MW), Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China (YC)
Published in Atlas Database: September 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/ERGIC3ID42222ch20q11.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62258/09-2014-ERGIC3ID42222ch20q11.pdf DOI: 10.4267/2042/62258
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Local order: ERGIC3 is located on the forward strand of chromosome 20 at 20q11.22 (figure 1.A). Review on ERGIC3, with data on DNA/RNA, on the It is between base pairs 35542029-35557634 (figure protein encoded and where the gene is implicated. 1.B) and is composed of 15606 nucleotides encoding Keywords 13 or 14 exons (figure 2). NCBI gene ID is 51614. ERGIC3; Erv46. Note According to hg38/GRCh38-Dec_2013: (GRCh38) Identity - ERGIC3 at chr20: 35542029-35557634 (NM_198398) endoplasmic reticulum-Golgi Other names: C20orf47, CGI-54, Erv46, NY-BR- intermediate compartment protein 3 isoform 1 84, PRO0989, SDBCAG84, dJ477O4.2 - ERGIC3 at chr20: 35542029-35557634 HGNC (Hugo): ERGIC3 (NM_015966) endoplasmic reticulum-Golgi Location: 20q11.22 intermediate compartment protein 3 isoform 2
Figure 1. ERGIC3 chromosomal localization (A) (adapted from GeneCards) and the ERGIC3 gene maps on chromosome 20q11.22 (B). The red line is the location of ERGIC3 on chromosome 20 (chr20).
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 499 ERGIC3 (ERGIC and golgi 3) Wu M, Cao Y
Figure 2. The transcript variants and coding sequence (CDS) of ERGIC3.
lumen area (43~344) from amino acid residues DNA/RNA (figure 3). Human ERGIC3 consists of 383 amino Note acid with the molecular mass 43.2 kD and the value According to hg38/GRCh38-Dec_2013:(GRCh38) of theoretical isoelectric point 5.68, (Geng et al., - Start: chr20: 35542029 bp from pter 2014). - End: chr20:35557634 bp from pter ERGIC3 protein contains two conserved domains, - Size: 15606 bases ERGIC_N and COPIIcoated_ERV (figure 3) which - Orientation: forward strand. are localized to the early secretory pathway and are involved in protein maturation and processing in the Transcription endoplasmic reticulum and/or sorting into COPII Two alternatively spliced transcript variants vesicles for transport to the Golgi (Otte et al., 2001). encoding different isoforms have been demonstrated There are 2 glycosylation sites in the N241, N266 for this gene. (figure 3). Isoform 1 transcript is 1383 bases (RefSeq: Description NM_198398.1), which is comprised of 14 exons and coding the longer isoform (Figure 2). 388 aa (Accession: NM_198398.1, NP_938408 ) Isoform 2 represents the shorter 1368 bases, RefSeq: isoform 1; 383 aa (Accession: NM_015966.2, NM_015966.2, which is comprised of 13 exons and NP_057050.1). isoform 2. ERGIC3 belongs to the coding the shorter isoform (Figure 2). The open family of the ER vesicle (Erv) proteins (Otte et al., reading frame (ORF) is shifted because the variant is 2001). ERGIC3 interacts with ERGIC2 (Welsh et al., not spliced. Therefore, compared to isoform 1 the 2006) and ERGIC1 (Breuza et al., 2004) and forms protein is shorter. a heterotrimeric protein complex. Both isoforms contain ERGIC_N domain and COPIIcoated_ERV Pseudogene domain (figure 3) which is conserved from fungi to No observed pseudogenes. humans. ERGIC3 works in close on junction with ERGIC2 Protein and together they form a complex which cycles between the endoplasmic reticulum and cis-Golgi Note network. Both are integral membrane proteins with Human ERGIC3 protein is a type II transmembrane two membrane spanning segments each, short N- protein containing two external membrane areas and C-terminal tails expose to the cytosol, and large (1~19, 368~383), two transmembrane areas (20~42, central luminal domains (figure 3) (Welsh et al., 341~362), as well as a endoplasmic reticulum 2006).
Figure 3. The domains of ERGIC3 protein (adapted from NCBI). aa: amino acid; posttrans. modifi.: posttranslational modification. TM: transmembrane domain.
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Expression No observed mutation sites. In normal human tissues, ERGIC3 is found in some epitheial cells such as liver, pancreas, stomach, Implicated in intestine, and so on, but is undetected in lung, Non-small cell lung cancer (NSCLC) cerebral cortex, cerebellum, heart, spleen, thymus, muscle (Lin, 2014). Note In human tumor tissues, ERGIC3 is highly expressed ERGIC3 is highly up-regulated in NSCLC. A study in lung cancer, hepatocellular carcinoma, pancreatic (Wu et al., 2013) demonstrated that ERGIC3 was carcinoma, gastric carcinoma, colon cancer, positive in 89% of NSCLCs while ERGIC3 was not esophagus cancer, but is negative in osteosarcoma, detected in normal bronchial epithelial cells and chondrosarcoma, and fibrosarcoma by alveolar cells. immunohistochemical (IHC) staining (Lin, 2014). Moreover, the positive rate of lung adenocarcinoma In addtion, ERGIC3 is highly expressed in the spinal was higher than that of lung squamous cell cord and kidney of mouse (Nishikawa et al., 2007). carcinoma, and the positive rate of poorly differentiated NSCLCs was higher than that of the Localisation well and moderately differentiated NSCLCs. ERGIC3 mainly localizes to endoplasmic reticulum, The study suggested that ERGIC3 may be a potential endoplasmic reticulum-golgi intermediate biomarker for lung cancer. compartment (ERGIC) and cis-Golgi network, Additionally, the over-expression of ERGIC3 (Breuza et al., 2004; Orci et al., 2003; Wu et al., promotes the cell proliferation, migration, and 2013). invasion in NSLCs (Wu et al., 2013). Function Hepatocellular carcinoma (HCC) The precise function of ERGIC3 is presently unclear, Note especially in mammal cells. There is a strong ERGIC3 was up-regulated in HCC. interaction between ERGIC3 and ERGIC2 so as to The over-expression of ERGIC3 modulates the form a heteromer complex which exerting its epithelial to mesenchymal transition (EMT), and biological function. The complex may be involved in increases the cell proliferation, migration, and : 1) the sorting of some secretory molecules during invasion in HCCs (Zhang et al., 2013). Furthermore, vesiclar transport (Belden and Barlowe, 2001; Otte ERGIC3 expression is regulated by MiR-490-3p and Barlowe, 2004) due to the hydrophobic signals (Zhang et al., 2013). present on both C-terminal tails of the ERGIC3- ERGIC2 complex control sorting into COPII References vesicles for anterograde transport, and retrieval from the Golgi is mediated by a COPI binding KKxx motif Otte S, Belden WJ, Heidtman M, Liu J, Jensen ON, Barlowe on ERGIC3 (Otte and Barlowe, 2002) ; 2) protein C. Erv41p and Erv46p: new components of COPII vesicles involved in transport between the ER and Golgi complex. J folding and glycoprotein processing in the Cell Biol. 2001 Feb 5;152(3):503-18 endoplasmic reticulum and cis- Golgi network Otte S, Barlowe C. The Erv41p-Erv46p complex: multiple (Nishikawa et al., 2007; Welsh et al., 2006). export signals are required in trans for COPII-dependent Glucosidase II is not transported into COPII vesicles transport from the ER. EMBO J. 2002 Nov 15;21(22):6095- in vitro as well as cells lacking a cycling ERGIC3- 104 ERGIC2 complex have a mild glycoprotein Orci L, Ravazzola M, Mack GJ, Barlowe C, Otte S. processing defect and a partial loss of glucosidase Mammalian Erv46 localizes to the endoplasmic reticulum- (Leah, 2006) inhibiting endoplasmic reticulum stress Golgi intermediate compartment and to cis-Golgi cisternae. (ERS)-induced cell death by tunicamycin in HEK- Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4586-91 293 cells (Nishikawa et al., 2007). Breuza L, Halbeisen R, Jenö P, Otte S, Barlowe C, Hong W, Hauri HP. Proteomics of endoplasmic reticulum-Golgi Homology intermediate compartment (ERGIC) membranes from ERGIC3 is highly conserved in species. The amino brefeldin A-treated HepG2 cells identifies ERGIC-32, a new cycling protein that interacts with human Erv46. J Biol acid sequence is at least 98% among 8 vertebrates, Chem. 2004 Nov 5;279(45):47242-53 human, pongo, macaca, ailuropoda, myotis, bovini, mus, heterocephalus. There is only one change in Welsh LM, Tong AH, Boone C, Jensen ON, Otte S. Genetic and molecular interactions of the Erv41p-Erv46p complex amino acid (T164) between human and pongo, 2 involved in transport between the endoplasmic reticulum changes in amino acid (T112, W170) between and Golgi complex. J Cell Sci. 2006 Nov 15;119(Pt human and macaca (Geng et al., 2014). 22):4730-40 Nishikawa M, Kira Y, Yabunaka Y, Inoue M. Identification Mutations and characterization of endoplasmic reticulum-associated protein, ERp43. Gene. 2007 Jan 15;386(1-2):42-51 Note
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Wu M, Tu T, Huang Y, Cao Y. Suppression subtractive bioinformatics analysists of hERGIC3 protein. J mod med hybridization identified differentially expressed genes in health.2014;30:2404-2406. lung adenocarcinoma: ERGIC3 as a novel lung cancer- related gene. BMC Cancer. 2013 Feb 1;13:44 Lin Q.. Preparation and identification of ERGIC3 monoclonal antibody and preliminary application research. Zhang LY, Liu M, Li X, Tang H. miR-490-3p modulates cell Beijing: Graduate University of Chinese Academy of growth and epithelial to mesenchymal transition of Sciences. 2014. hepatocellular carcinoma cells by targeting endoplasmic reticulum-Golgi intermediate compartment protein 3 This article should be referenced as such: (ERGIC3). J Biol Chem. 2013 Feb 8;288(6):4035-47 Wu M, Cao Y. ERGIC3 (ERGIC and golgi 3). Atlas Genet Geng N, Wu M, Zheng X, Liu X, Li X.. Construction of Cytogenet Oncol Haematol. 2015; 19(8):499-502. prokaryotic expression vector with hERGIC3 gene and the
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Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Review
NFE2L2 (nuclear factor, erythroid 2-like 2) Stavroula D Manolakou, Panos G Ziros, Gerasimos P Sykiotis Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland (SDM, PGZ), Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, Switzerland (GPS)
Published in Atlas Database: September 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/NFE2L2ID44284ch2q31.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62259/09-2014-NFE2L2ID44284ch2q31.pdf DOI: 10.4267/2042/62259 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
hypermethylation and repression of gene expression Abstract (Kwak et al., 2002; Hayes and Dinkova-Kostova, Review on NFE2L2, with data on DNA/RNA, on the 2014). protein encoded and where the gene is implicated. Identity Other names: NRF2 HGNC (Hugo): NFE2L2 Location: 2q31.2 Note The transcription factor Nrf2, encoded by the NFE2L2 gene, is the mediator of a cellular antioxidant response. Nrf2 belongs to the cap'n'collar (cnc) family of transcription factors. DNA/RNA Description The NFE2L2 gene is approximately 34.8 kb in size. The mouse homologue of the NFE2L2 gene is a self- and hetero-inducible gene; its promoter region contains two ARE/EpRE (antioxidant or electrophile response element) sequences at -492 bp and -754 bp, through which it is induced by Nrf2. In addition, its regulatory region contains three XRE (xenobiotic response element) sequences at -712 bp, +755 bp and +850 bp. ARE and XRE sequences are implicated in the inducible upregulation of the gene¡s transcription. A kB2 region for NF-κB binding has NFE2L2 gene - transcript variants. NFE2L2 gene located on chromosome 2. Multiple transcript variants (TV) been detected at +270 bp; proinflammatory stimuli encoding different isoforms have been found for this gene. can induce human NFE2L2 transcription via this The transcript variants referenced more often in the element. On the other hand, five CpG sequences in literature are NM_006164.4 (TV 1), NM_001145412.2 (TV the promoter region of NFE2L2 allow 2) and NM_001145413.2 (TV 3).
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 503 NFE2L2 (nuclear factor, erythroid 2-like 2) Manolakou SD, et al.
Structural and functional domains of Nrf2. A. Structural features of the human Nrf2 protein that dictate its activity. The interaction with Keap1 is mediated by the Neh2 (Nrf2 extended homology 2) domain of Nrf2. B. Nuclear localisation signals (NLS) and nuclear export signals (NES) have been detected in the Nrf2 sequence. The NESTA motif is the only one shown to be directly redox-sensitive. C. Specific cysteine residues have been characterised as reactive, meaning that they are sensitive to oxidation. Oxidative stress also activates intracellular kinases such as PKC and Fyn which in turn phosphorylate Nrf2 (on Ser40 and Tyr568, respectively) contributing to Nrf2 activation (Jain et al., 2005; Zhang, 2006).
Transcription 67.8 kDa in weight and consists of 605 amino acids; NP_001138884.1 (encoded by TV2) is 66.1 kDa in NM_006164.4 (TV 1) comprises 5 coding exons and weight and consists of 589 amino acids; and is approximately 2.8 kb in size; this transcript NP_001138885.1 (encoded by TV3) is 65.4 kDa in encodes the longest protein isoform. size and consists of 582 amino acids. NM_001145412.2 (TV 2) and NM_001145413.2 Nrf2 has been characterized as a modulator protein (TV 3) comprise 4 coding exons each and are and is the core of the Nrf2 antioxidant approximately 2.7 kb and 2.4 kb in size, respectively. system/pathway. Other main components of the MiRNAs pathway are Keap1, the negative regulator of Nrf2, miRNA3128 is a non-coding RNA that is the and small Maf proteins which serve as cofactors for transcript product of a region in the first intron of Nrf2 binding to regulatory DNA sequences of ARE- NFE2L2 (chr. 2: 177255945-177256010, regulated genes (Moi et al., 1994; Li and Kong, complement). It is not known whether it has a role in 2009). the regulation of NFE2L2 expression. Micro RNAs species reported to suppress NFE2L2 expression Description include miR-27a, miR-28, miR-34a, miR-93, miR- 142-5p, miR-144, and miR-153 (Filipowicz et al., Nrf2 binds to ARE sites of antioxidant genes as a 2008; Cheng et al., 2013; Hayes and Dinkova- heterodimer. Specifically, Nrf2 heterodimerizes with Kostova, 2014). small Maf proteins (which are themselves devoid of transcription activating domains) to induce the Protein transcription of ARE-regulated genes. Other binding partners include members of the AP-1 transcription Note factor family like Jun and Fos. In contrast, Name: Nuclear factor erythroid 2-related factor 2. homodimers or heterodimers of the different small Short: NF-E2-related factor 2, NFE2-related factor Maf proteins, and heterodimers of Bach proteins 2. with small Maf proteins on AREs, have been Alternatives names: Nuclear factor, erythroid characterised as negative regulators of Nrf2 derived 2, like 2, NF-E2 p45-related Factor-2. signalling pathway that compete with Nrf2 for Nrf2, the nuclear factor erythroid 2 (NF-E2)-related binding to AREs. The co-factor CBP/p300 is transcription factor 2, was first described in 1994 by indispensable for transcription activation by Nrf2 Moi et al. by screening for factors that could bind to and localizes to ARE-binding sites in association a NFE2-binding DNA sequence. The human Nrf2 with Nrf2-small Maf heterodimers protein NP_006155.2 (encoded by TV 1) is (Dhakshinamoorthy et al., 2005; Ishikawa et al., 2005; Li et al., 2008; Hirotsu et al., 2012).
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NFE2L2 (nuclear factor, erythroid 2-like 2) Manolakou SD, et al.
Crystal structures of the Nrf2-binding domain of Keap1 (Keap1 DC/Kelch domain) in complex with peptides derived from the Keap1-binding domain of Nrf2 (the DLG motif of the mouse Neh2 domain or the ETGE motif of the human Neh2 domain).
Expression Oxidative stress and the antioxidant Nrf2 is considered to be ubiquitously expressed, as it transcriptional response mediated by Nrf2 has been shown to be expressed in various cell types Cells and tissues are constantly exposed to various (including lung, liver, kidney, stomach, small oxidative substances and electrophilic chemicals, intestine, neurons, astrocytes, etc) and it has been including reactive oxygen species (ROS) and considered a multi-organ protector that enhances the reactive nitrogen species (RNS), derived from both cellular resistance to potential harmful insults that endogenous and exogenous sources. To adapt to the occur during cells' normal activities and during oxidative environment, cells have developed environmental exposures. Morevoer, Nrf2 has been elaborate and highly efficient antioxidant found to be overexpressed in various human cancers machineries. When pro-oxidant and electrophilic (Yoo et al., 2012; Lee and Surh, 2005). challenges overwhelm the cell's antioxidant and Localisation detoxification proteins, cells experience oxidative Nrf2 can be detected both in the cytoplasm and in the stress. Oxidative stress conditions can cause damage nucleus; the Keap1-mediated degradation of Nrf2 to cellular structures, including lipids, proteins, and occurs in the cytoplasm. In addition, one of the nucleic acids. Among other injuries, this can lead to proposed models for the Keap1-Nrf2 interaction mutations and epigenetic perturbations by damaging suggests that a Keap1 dimer can bind one Nrf2 DNA and proteins that modify chromatin. Thus, molecule and one PGAM5 molecule. PGAM5 oxidative stress can be a causative or exacerbating possesses a N-terminal membrane targeting signal, factor in a range of diseases, including, for example, through which the Nrf2-Keap1-PGAM complex is respiratory and metabolic disorders, tethered to the cytosolic surface of the outer neurodegenerative diseases, and cancer. mitochondrial membrane. As a result, Nrf2 can be In order to maintain homeostasis in the face of also localised in the perimitochondrial region oxidative insults, cells possess signalling pathways (Sykiotis and Bohmann, 2010). that can sense oxidative stress and launch adaptive responses. Multiple ways of managing the Function intracellular oxidative load have been identified over The Nrf2/Keap1 pathway is a major mediator of the last two decades; among them, it has been cytoprotective responses to oxidative and recognized that gene transcription can be regulated electrophilic stress. Nrf2 responds to oxidative stress by redox reactions. Prominent among the redox- by inducing the transcriptional upregulation of a sensitive pathways of gene activation is the Nrf2 broad range of cytoprotective genes whose system. The core of this pathway comprises the promoters contain Antioxidant Response Element transcription factor Nrf2 and its negative regulator (ARE) sequences. Specifically, Nrf2 translocates to Keap1. In addition, small Maf proteins serve as the nucleus, heterodimerizes with small Maf proteins dimerization partners of Nrf2 to facilitate its binding and binds to ARE sequences to induce gene to DNA on special sequences termed antioxidant transcription. When redox balance is restored, Nrf2 response elements (AREs) or activity is repressed via export from the nucleus back electrophile response elements (EpREs) in the into the cytoplasm and degradation via a Cullin - regulatory regions of the many Nrf2-regulated RING ligase 3 - Keap1 complex (CRLkeap1 genes, including the genes encoding glutamate complex), and by other mechanisms (Zhang, 2006). cysteine ligase catalytic subunit (GCLC), heme
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oxygenase-1 (HO-1), NADP(H) quinone The sensing mechanisms comprise oxidation or oxidoreductase-1 (NQO1), microsomal glutathione- alkylation of critical Keap1 cysteine residues S-transferases such as MGST1 and MGST2, and (including Cys151, Cys273 and Cys288), and multi-drug resistance-associated proteins such as phosphorylation of Nrf2 on amino acids Ser40 and ATP-binding cassette, subfamily C (CFTR/MRP), Tyr568 (Zhang and Hannink, 2003; Yamamoto et member 1 (ABCC1) (Magesh et al., 2012; Hayes and al., 2008; Magesh et al., 2012). Dinkova-Kostova, 2014). When redox homeostasis is restored, Nrf2 activity is Activity and regulation of Nrf2 repressed via export from the nucleus back into the The Nrf2 pathway responds to oxidative stress by cytoplasm and degradation via a Cullin-RING ligase inducing the transcriptional upregulation of a broad 3 - Keap1 complex (CRLkeap1 complex). Nrf2 can range of cytoprotective genes. also trigger a feedback loop of increased expression The Nrf2 system responds to both endogenous of ARE-dependent genes including Keap1 and Cul3, reactive molecules, such as reactive oxygen species which then promote Nrf2 degradation and thus (ROS) and reactive nitrogen species (RNS), and to participate in resetting Nrf2 activity at its basal level (Rachakonda et al., 2008; Eggler et al., 2009; Baird exogenous substances. and Dinkova-Kostova, 2011).
A. Keap1 binds Nrf2 and inhibits its transcriptional activity. The depicted "hinge-and-latch" model proposes a 2:1 Keap1:Nrf2 molecular stoichiometry. B. At the basal cellular state (low oxidative burden), Nrf2 undergoes Keap1-Cul3-mediated poly- ubiquitination and proteasomal degradation.
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Two mechanistic models for the Nrf2-Keap1 interaction. Adapted from Sykiotis and Bohmann, 2010.
Activation of Nrf2 pathway In general, the effects of the intracellular events A. Transcriptional induction of the NFE2L2 gene induced by Nrf2 activation lead to NF-κB A1. Nrf2 autoregulation suppression, and vice versa; thus, overall, Nrf2 It has been shown that the promoter of the mouse signaling antagonises NF-κB signaling. orthologue of the NFE2L2 gene includes two Nevertheless, in acute myeloid leukemia it has been antioxidant response element-like sequences (ARE- reported that Nrf2 is upregulated by NF-κB- L1 and ARE-L2), which are located at -492 bp and - mediated transactivation of the NFE2L2 gene by 754 bp from the transcription start site, respectively. direct binding of NF-κB to the NFE2L2 promoter It has been proposed that under stress conditions (Rushworth et al., 2012). newly translated Nrf2 protein escapes Keap1- The AhR/ARNT complex (aryl hydrocarbon mediated degradation and binds to the ARE-L1 and receptor / AhR nuclear translocator) regulates gene ARE-L2 sequences to induce NFE2L2 gene transcription in response to xenobiotics, such as transcription in a feed-forward manner (Shin et al., polycyclic aromatic hydrocarbons, via binding to 2007; Hayes and Dinkova-Kostova, 2014). xenobiotic response elements (XREs). Three XRE- A2. NFE2L2 transcription induced by the like elements have been identified in the mouse oncoproteins K-Ras and B-Raf Nfe2l2 promoter; via these elements, the AhR/XRE It has been demonstrated that oncogene-directed pathway can control Nrf2/ARE signaling (Miao et increased expression of the NFE2L2 gene can be an al., 2005). alternative mechanism of Nrf2 activation. K-Ras and A4. BRCA1 / ARNT-mediated induction of B-Raf, which operate in the mitogen-activated NFE2L2 gene transcription protein kinase (MAPK) pathway, have been shown The transcription factor BRCA1 (breast cancer 1, to increase NFE2L2 transcription via activation of early onset) has been reported to increase the Jun or/and Myc. It has been proposed that via this transcription of the NFE2L2 gene. As BRCA1 has mechanism oncogenic signaling may modulate the ability to interact with ARNT, it is possible that redox homeostasis during tumirogenesis (DeNicola BRCA1 induces Nrf2 expression in an ARNT- et al., 2011). dependent manner (Kang et al., 2006). A3. Cross-talk of Nrf2 with the NF-κB and AhR B. Post-translational activation of Nrf2 signaling pathways
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B1. The "hinge and latch" and "quaternary" Furthermore, it has been found that PKC models phosphorylates Nrf2 at Ser-40 facilitating its release At basal conditions (meaning the absence of from Keap1-mediated inhibition (Wakabayashi et oxidative stress) the NFE2L2 gene is constantly al., 2010; Stepkowski and Kruszewski, 2011). transcribed and Nrf2 protein is constantly B3. The redox signaling "model of two Nrf2 synthesized, but Nrf2 protein abundance and activity pools" are maintained at low levels due to the negative Multiple NLS/NES (Nuclear localisation signal/ regulation of Nrf2 by Keap1 through the CRLkeap1 nuclear export signal) motifs have been identified in complex. the Nrf2 sequence. These include three NLS motifs The "hinge and latch" model has been proposed as a (bNLS, NLSN and NLSc) and two NES motifs mechanistic model that accounts for the interaction (NESTA and NESZIP) but only the NESTA motif has between Nrf2 and Keap1 and provides as structural been found to be redox-sensitive. Specifically, the basis for the Keap1-dependent polyubiquitination NESTA motif has been shown to display a graded and degradation of Nrf2. This model posits an response to oxidative stress, implying that it can not interaction of one Nrf2 molecule with a Keap1 only sense the presence of reactive oxidative species, homodimer, in which the high affinity binding of the but it also has the ability to transmit the oxidative ETGE motif of the Neh2 domain of Nrf2 functions stress "intensity" to the nucleus in order to up- as a "hinge" to fix Nrf2 to one of two Keap1 regulate the transcription of ARE-genes accordingly. molecules, whereas the low affinity binding of the Based on these observations, Nrf2 has been proposed DLG motif of the Neh2 domain of Nrf2 functions as as a direct redox-sensor. Specifically, under basal a "latch" to lock down the Neh2 domain to the other condition a dynamic balance can be observed as the Keap1 molecule of the homodimer. The fixation of combined nuclear exporting forces of NESTA and the Neh2 domain between the two Keap1 molecules NESZIP counteract the combined nuclear importing thus facilitates its ubiquitination and the subsequent force of the bNLS, NLSN and NLSc leading to a degradation of Nrf2 by the 26S proteasome. A whole-cell distribution of Nrf2. However, under competing structural model is the "quaternary oxidative stress the NESTA is functionally disabled, complex" model, which proposes that a Keap1 dimer and the driving force of NLSs becomes dominant binds two molecules of substrate through high- and favors the nuclear localization of Nrf2. affinity interactions with ETGE motifs. Specifically, The NLS/NES motifs and their role in activation of a Keap1 dimer can bind two Nrf2 molecules, or one Nrf2 have led to the hypothesis for Keap1- Nrf2 molecule and one PGAM5 molecule. PGAM5 independent Nrf2 signaling. Nevertheless, this possesses an N-terminal membrane targeting signal model does not exclude Keap1 involvement in redox through which the Nrf2-Keap1-PGAM complex is signaling. Consequently, a new model has been tethered to the cytosolic surface of the outer proposed that encompasses both Keap1-dependent mitochondrial membrane (Tong et al., 2006; Sykiotis and Keap1-independent Nrf2 signaling. This model and Bohmann, 2010; Kansanen et al., 2012), proposes that in cells there may exist a free-floating potentially to allow Nrf2 to be activated in response pool of Nrf2 (fNrf2) and a Keap1-bound pool of Nrf2 to mitochondrial leakage of ROS. (kNrf2). Under homeostatic conditions there is an Under conditions of oxidative stress, it is believed equilibrium between synthesis and degradation of that the oxidative modification of certain cysteine Nrf2, such that the fNrf2 pool remains small. But residues of Keap1 leads to conformational changes when cells are exposed to oxidative stress, the Nrf2- of the Keap1 dimer. In the "hinge and latch" model, binding capacity of Keap1 is diminished and the this results in dissociation of the DLG motif from fNrf2 pool is enlarged. As the NESTA of the fNrf2 Keap1, wuch that Nrf2 cannot be properly presented redox-sensitive pool is disabled by the stress, nuclear for ubiquitination by the CRLkeap1 complex and thus localization of Nrf2 is favored (Li and Kong, 2009). escapes proteosomal degradation. The stabilized B4. Competitors of Nrf2 for binding to Keap1 Nrf2 accumulates in the nucleus where it It has been demonstrated that the ability of Keap1 to heterodimerizes with small Maf proteins and binds repress Nrf2 can be modulated by proteins that also to AREs, leading to transcription of ARE-dependent possess ETGE motifs and thereby compete with cytoprotective genes (reviewed in Sykiotis and Nrf2 for the same binding site in Keap1. For Bohmann, 2010; Hayes and Dinkova-Kostova, example, dipeptidyl-peptidase 3 (DPP3), IκB kinase 2014). β (IKKβ), partner and localizer of BRCA2 (PALB2), B2. Phosphorylation of Nrf2 by PKC phosphoglycerate mutase 5 (PGAM5) and Wilms Several protein kinases, including protein kinase C tumor gene on X chromosome (WTX) contain (PKC), have been implicated in the upstream ETGE motifs that enable them to bind Keap1 and act regulation of Nrf2 pathway. Specifically, as competitors of Nrf2 (Hayes and Dinkova- phosphorylation of Nrf2 by PKC induces nuclear Kostova, 2014). translocation of this transcription factor and B5. mTOR signaling and p62-dependent activation of the ARE in response to oxidative stress. degradation of Keap1
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There is also cross-talk between Nrf2-Keap1 CRLkeap1complex, and the nucleocytoplasmic signaling and autophagy. It has been shown that in shuttling of Keap1 (Rachakonda et al., 2008; Eggler normal cells this interaction serves as a host defence et al., 2009; Baird and Dinkova-Kostova, 2011). mechanism leading to expression of antioxidant Repression of Nrf2 signaling enzymes as well as elimination of cytotoxic A. Transcriptional repression of the NFE2L2 products. Keap1 can bind the autophagy cargo gene receptor p62, which contains an STGE motif similar A CpG island has been identified in the 5' flanking to the ETGE motif of Nrf2. Following region of the NFE2L2 gene that extends to position phosphorylation of Ser 351 within its STGE motif by -1175. The first 5 CpGs in this CpG island are found the mammalian target of rapamycin complex to be hypermethylated in prostate cancer samples (mTORC1), p62 becomes a potent inhibitor of and prostate cancer cell lines compared to normal Keap1. p62 is phosphorylated by mTORC1 in the prostate issues and cells. This hypermethylation presence of ubiquitinated autophagic cargos, which leads to repression of NFE2L2 gene expression, can occur under oxidative conditions; this in turn potentially favouring tumorigenesis (Yu et al., favors the binding of Keap1 to the phosphorylated 2010). STGE motifs. As a result, Keap1 is sequestrated in B. Post-transcriptional repression of Nrf2 autophagy cargos in a p62-dependent manner, At the post-transcriptional level, various micro allowing Nrf2 to be stabilized and to accumulate in RNAs (miRNAs) have been identified to interact the nucleus to induce cytoprotective enzymes with the Nrf2 mRNA resulting in repression of Nrf2 (Komatsu et al., 2010; Ichimura et al., 2013; expression, including miR-27a, miR-28, miR-93, Lamming and Sabatini, 2013). miR-142-5p, miR144 and miR-153 (Hayes and B6. Cross-talk between p53/p21 and the Nrf2 Dinkova-Kostova, 2014). pathway C. Post-translational repression of Nrf2 The p53 tumor suppressor protein regulates several C1. CRLkeap1 complex-mediated degradation of intracellular procedures including gene transcription Nrf2 and induction of apoptosis. It has been demonstrated As mentioned, the CRLkeap1 complex is responsible that p53 is implicated in the regulation of the Nrf2- for the ubiquitination and 26S degradation of Nrf2 mediated oxidative response in a dual manner: under under normal conditions. Keap1 acts as an adaptor low or mild levels of oxidative stress, p53 promotes protein to mediate the interaction between Nrf2 and the stabilization of Nrf2 and its subsequent nuclear the Cul3 E3-ligase enyme, resulting in ubiquitination accumulation through the transcriptional activation of lysines residues of the region located between the of p21, and as a result reduces the oxidative burden ETGE and DLG motifs in the Neh2 domain. to promote cell survival. p21 stabilizes Nrf2 due to Thereafter, ubiquitinated Nrf2 undergoes the existence of a KRR motif within the p21 degradation by the 26S proteosome. It has been sequence which interacts with the DLG motif of reported that the Nedd8 molecule serves as a factor Nrf2 inhibiting its binding to Keap1. On the other of stabilization of the CRLkeap1 complex, and that the hand, under conditions of high or sustained levels of removal of Nedd8 by the CSN signalosome causes oxidative stress, Nrf2-mediated cell survival is disruption of the complex and inhibition of Nrf2 suppressed, and high activity levels of p53 induce ubiquitination. CAND1 is a mediator protein that can apoptosis to prevent tumorigenesis (Chen et al., also block the degradation process of Nrf2 2009; Chen W et al., 2012). (Villeneuve et al., 2010). B7. Competitive binding of BRCA1 to Nrf2 C2. Crm1-dependent nuclear export and β- The ability of Keap1 to repress Nrf2 can be TrCP-dependent degradation of Nrf2 diminished by the competitive binding of breast Nrf2 degradation by Keap1 is mediated by cancer protein BRAC1, thereby preventing Keap1 interaction via the Nrf2 Neh2 ETGE and DLG from simultaneously binding to the ETGE motif of motifs. Nevertheless, in Nrf2 proteins mutant for the Nrf2 (Gorrini et al., 2013). ETGE and DLG motifs, it has been observed that the B8. Acetylation of Nrf2 by p300/CBP Neh6 domain accounts for some of the residual It has been found that acetylation of the Neh1 instability of Nrf2 in a Keap1-independent way. domain of Nrf2 can increase the binding affinity of Specifically, it has been shown that the DSGIS and Nrf2-Maf heterodimers for ARE sequences. DSAPGS motifs located within the Neh6 domain p300/CBP acetylates lysine residues of the Neh1 serve as binding sites through which Nrf2 binds with domain and enhances the interaction between Nrf2 β-TrCP. β-TrCP has the ability to target Nrf2 for and ARE sequence of antioxidant genes promoter ubiquitination and degradation through a Skp1- resulting in induction of the respective genes' Cul1-Rbx1/ Roc1 ubiquitin ligase complex; in vitro transcription (Sun et al., 2009). experiments with fibroblasts where β-TrCP is Other mechanistic models which have been knocked down have shown increased Nrf2 protein proposed for Nrf2 stabilization and activation levels. include the oxidation-induced dissociation of the
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This mechanism participates in the post-induction protein 4 (RNF4) ubiquitinates the pNrf2 leading it regulation of Nrf2 activity. The serine/threonine to degradation within the nucleus (Hayes and kinase GSK-3 controls the activity of the nuclear Dinkova-Kostova, 2014). kinase Fyn which in turn phosphorylates Tyr568 of C4. Negative feedback loops regulating Nrf2 Nrf2 and promotes its Crm1 (exportin)-mediated In vitro experiments have shown that antioxidant export from the nucleus. GSK-3-mediated Fyn treatment can induce the expression of Keap1, phosphorylation also causes an increase of the suggesting a possible role of Nrf2 in the regulation DSGIS degron activity in the Neh6 domain. The of Keap1 expression. latter results in β-TrCP binding to the Neh6 domain Keap1 has three ARE sequences within its promoter, of Nrf2 and consequently in β-TrCP-mediated Nrf2 of which one ARE on the reverse strand (position - degradation (Jain and Jaiswal, 2007; Chowdhry et 46) has been demonstrated to be functional in al., 2013). facilitating KEAP1 gene transcription. Thus, it has C3. Repression of Nrf2 by CRIF1, SIAH2 and been suggested that Nrf2 can control its own RNF4 degradation by binding to the Keap1 ARE(-46) and The CR6-interacting factor 1 (CRIF1) can promote thereby inducing KEAP1 transcription. the ubiquitination of Nrf2 through its interaction In other words, there exists an autoregulatory loop in with both the N-terminal Neh2 and C-terminal Neh3 which Nrf2 controls Keap1 at the transcriptional domains of Nrf2. The physiological circumstances level and Keap1 regulates Nrf2 at the post- when CRIF1 represses Nrf2 activity remain obscure. translational level (Lee et al., 2007). During hypoxia, it has been observed that SIAH2 Similarly, it has been observed that Nrf2 regulates can lead to Nrf2 ubiquitination in a Neh2- the expression of the Cul3 and Rbx1 genes. independent manner. Further work is required to The Cul3 and Rbx1 proteins are constituents of the elucidate the basis of interaction between SIAH2 and CRLkeap1 complex which is responsible for the Nrf2 and the conditions that regulate it. ubiquitination of Nrf2. It has been reported that small ubiquitin-like Specifically, it has been found that both the Cul3 modifiers 1 and 2 (SUMO-1, SUMO-2) gene promoter and the Rbx1 gene promoter contain polysumoylate Nrf2 in promyelocytic leukemia one functional ARE, and that Nrf2 acts in an autoregulatory way by binding to these AREs to nuclear bodies. regulate the expression of the Cul3 and Rbx1 genes The polysumoylated Nrf2 (pNrf2) translocates into (Kaspar and Jaiswal, 2010). the nucleus where SUMO-specific RING finger
Schematic overview of the main steps in the regulation of the Keap1-Nrf2 antioxidant response pathway. Adapted from Sykiotis and Bohmann, 2010.
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A phylogenetic tree of the Cnc and Bach transcription factors. A multiple species alignment was constructed with ClustalW (www.ebi.ac.uk/clustalw), and a phylogenetic tree was generated with the Jalview applet. The tree was based on the largest gap- free block of aligned sequences, which contained the DNA binding domains of the Cnc and Bach factors. Accession numbers: mouse p45 NFE2, NP_032711.2; mouse Nrf1, NP_032712.2; mouse Nrf2, NP_035032.1; mouse Nrf3, NP_035033.1; mouse Bach1, NP_031546.1; mouse Bach2, NP_001103131.1; Drosophila CncC, NP_732833.1; C. elegans SKN-1, NP_741404.1 (Sykiotis and Bohmann, 2010).
In addition, there is evidence that Nrf2 is implicated best studied cnc proteins are the C. elegans SKN-1 in the expression of genes encoding 26S proteasome (Skin family member 1), the D. melanogaster Cnc subunits, presumably in order to increase the (isoforms B and C), and four vertebrate counterparts: proteasome-dependent removal of oxidatively the p45 NFE2 (nuclear factor erythroid-derived 2) damaged proteins. Therefore, it has been proposed and the NFE2-related factors Nrf1, Nrf2 and Nrf3 that Nrf2 may regulate this negative autoregulatory ("the Nrfs"). In addition, the related transcription feedback loop via the proteasome to restore its levels factors Bach1 and Bach2 are characterised by the to the basal state after the removal of oxidative additional presence of a BTB protein interaction stimuli (Chapple et al., 2012). domain (Sykiotis and Bohmann, 2010). Furthermore, it is known that Bach1 competes with Although most Cnc factors are transcriptional Nrf2 for binding to the ARE-sequence of Nrf2- activators, Bach1 and Bach2 function mainly regulated genes. It has been demonstrated that Bach1 (through not exclusively) as transcriptional transcript variant 2 has an intronic ARE sequence repressors (figure below). Some of the Cnc proteins (position +1411) and can be a transcriptional target have important roles in development; for example, gene of Nrf2 (negative autoregulatory feedback CncB is required for the development of head mechanism) (Jyrkkänen et al., 2011). segments in D. melanogaster. Other family members Finally, it has been recently discovered in cancer cell (including Nrf2) are dispensable for development lines that retinoid X receptor α (RXRα) serves as an but rather contribute to the maintenance of cellular inhibitor of Nrf2 that regulates Nrf2 activity through homeostasis in response to endogenous or a direct interaction with Neh7 domain, where a exogenous stressors. In particular, the three Nrfs RXRα-binding site has been mapped. As the have broad and partly overlapping expression activation of Nrf2 results in upregulation of RXRα, patterns and function as stress-activated this can form another negative feedback loop for transcription factors (Sykiotis and Bohmann, 2010). Nrf2 regulation (Wang et al., 2013). Homology Mutations Nrf2 belongs to a family of basic leucine zipper Somatic (bZip) transcription factors called cap'n'collar (cnc) proteins. Cnc proteins are defined by the presence of Somatic mutations of the NFE2L2 gene have been a conserved 43-amino acid cnc domain located N- detected in cancers. Mainly missense mutations and terminally to the DNA-binding domain (bZip in frame insertions/deletions of NFE2L2 localised in structure) and are conserved in invertebrates and the DLG and ETGE motifs of the Neh2 domain vertebrates but not present in plants or fungi. The cause modifications in Nrf2 protein that lead to
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impaired interaction of Nrf2 with Keap1, and Similarly, haemodialysis patients with the thereby to constitutive Nrf2 activation. rs35652124 TT genotype had higher diastolic blood Thus, the Nrf2 pathway is currently believed to have pressure and higher cardiovascular mortality than a role not only in cancer prevention via CC or CT carriers. detoxification and maintenance of cellular Finally, in a Netherlands population, it has been homeostasis, but also in the cell growth and survival demonstrated that carriers of the rs2364723 (G/C) of malignant or premalignant cells. NFE2L2 minor G allele showed lower triglyceride levels and mutations have been identified in oesophageal reduced risk of cardiovascular mortality. squamous cell carcinoma (8/70, 11.4%; 6/32, Gastrointestinal disorders 18.8%), skin cancer (1/17, 6.3%; 1/22, 4.5%), non- The rs6706649 C and rs35652124 C SNPs have small cell lung carcinoma (NSCLC, 6.9-10.7%), higher frequency in Japanese patients with ulcerative head and neck carcinoma (HN, 13-25%), cervical colitis, and their presence has been correlated with a cancer (1/18, 5.6%) and papillary renal cell chronic continuous disease phenotype. In carcinoma (2 cases). Helicobacter pylori-infected patients, the Interestingly, lung cancer, and particularly non- rs6706649C/rs35652124C and small cell lung cancer, has been investigated for rs6706649C/rs35652124T haplotypes have been NFE2L2 mutations in various patient populations, correlated with increased and decreased risk, and in all studies the presence of NFE2L2 mutations respectively, of CpG methylation; was positively correlated with smoking history. In rs6706649C/rs35652124T carriers with negative addition, it has been observed that the frequency of Helicobacter pylori test showed reduced risk of NFE2L2 gene mutations is higher in lung squamous gastric cancer. cell carcinoma than in lung adenocarcinoma (Shibata Autoimmune disorders et al., 2008a; Kim et al., 2010; Solis et al., 2010; In a Mexican Mestizo population it was found that Shibata et al., 2011; Hu et al., 2012; Gantildeán- lupus nephritis in women was significantly Gómez et al., 2013; Ooi et al., 2013). associated with presence of the heterozygous NFE2L2 polymorphisms rs35652124 (C/T). Specific polymorphisms associated with disease Breast cancer risk* Homozygosity for rs6721961 (TT) or rs2706110 Respiratory disorders (TT) has been associated with increased risk of Heterozygosity (T/G) for rs6721961 (T/C/G) has breast cancer in a Finish population. Moreover, been associated with increased risk of acute lung presence of the rs6721961 T allele together with the injury (ALI) in patients with major trauma in intronic rs1962142 A allele was associated with Caucasian/African-American and Japanese reduced Nrf2 expression in breast cancer tissue. In a populations. Paradoxically, in a Japanese cohort, the study of a Finish population, Nrf2 rs2886182 (T/C) haplotype (rs2001350T/rs6726395A/ rare homozygous genotype TT has been significantly rs1962142A/rs2364722A/rs6721961T) containing associated with poorer survival and recurrence-free the homozygous SNP rs6721961 TT has been survival in patients with breast cancer that had correlated with lower annual decline in forced received adjuvant chemotherapy, and with poorer expiratory volume in one second (FEV1), a measure survival in patients with breast cancer that had of pulmonary function. In contrast, the rs6726395 G undergone postoperative radiotherapy. allele showed association with higher annual decline Venous thromboembolism of FEV1 induced by cigarette smoking in Japanese. In postmenopausal women the rs6721961 (T allele) Furthermore, a haplotype containing rs35652124 C, increased the risk of venous thromboembolism after rs6706649 C, rs6721961 G and GGC4 (a repeat oral estrogen therapy. polymorphism) has been proposed as a predictor Neurodegenerative diseases factor of increased respiratory failure development In Swedish populations, a protective effect against in German patients with chronic obstructive Parkinson's disease has been detected for a haplotype pulmonary disease (COPD). A further study in a containing promoter SNPs rs7557529C/ Netherlands population showed correlations rs35652124T/ rs6706649C/ rs6721961G as well as between rs1806649 C and reduced COPD mortality, intronic SNPs rs2886161T/ rs1806649T/ and between the rs2364723 CC and reduced FEV1. rs2001350T/ rs10183914T) (Yamamoto et al., 2004; In a Hungarian population of childhood asthma, Marzec et al., 2007; Arisawa et al., 2008; Siedlinski rs6721961 T and rs2588882 G have been inversely et al., 2009; Masuko et al., 2011; Hartikainen et al., correlated with the infection-induced asthma. 2012; Cho, 2013; Figarska et al., 2014; Shimoyama Cardiovasular disorders et al., 2014). The rs6721961 TT genotype has been associated * The nucleotides for each SNP correspond to the with higher systolic and diastolic blood pressure in map on chr. 2, and are thus complementary to the Japanese haemodialysis patients than the CC or CT gene sequence (NFE2L2 lies on the reverse strand). genotypes.
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papillary thyroid cancer. Hypermethylation of CUL3 Implicated in and RBX1 genes as well as CUL3, RBX1 and Various cancers KEAP1 copy number losses have been proposed as further Nrf2 activation mechanisms in papillary The dual role of Nrf2: NFE2L2 has been found to thyroid carcinoma. have both cancer chemopreventive activity (by Moreover, Nrf2 expression and activation can be protecting cells from carcinogen-induced damage induced by Nrf2 cross-talk with other signalling and transformation) and oncogenic activity (by pathways. Specifically, it has been demonstrated that conferring a survival advantage to pre-malignant or in acute myeloid leukaemia (AML) Nrf2 malignant cells). Thus, on the one hand, activation of overexpression is driven by abnormal expression of Nrf2 upregulates various conjugating enzymes for Nuclear Factor-κB (NF-κB). In addition, in NSCLC the detoxification of chemical carcinogens and cell lines constitutive activation of mutant epidermal protects from carcinogenicity, mutagenicity and growth factor receptor (EGFR) and RagD-mediated other forms of toxicity. Experimental disruption of activation of mammalian target of rapamycin (m- Nrf2 is associated with increased susceptibility of TOR) signalling pathway cause overactivation of cells to carcinogens. The chemopreventive Nrf2 as well as Nrf2-mediated resistance to EGFR- properties of Nrf2 have been demonstrated in several tyrosine kinase inhibitor and m-TOR inhibitor, experimental models of cancer including colon, respectively. In renal cancer cells, Nrf2 activity has bladder, lung, stomach, breast, skin and liver cancer. been found to be increased by downregulation of E- Importantly, inducers of Nrf2 pathway are being cadherin which normally forms a quanternary tested in clinic trials for cancer chemoprevention. complex with Nrf2, Keap1 and β-catenin and On the other hand, in various cancers Nrf2 protein facilitates Keap1-mediated ubiquitination of Nrf2. abundance and activity have been found to be Finally, it has been observed that transcriptional increased, suggesting a role in tumour growth and coactivator amplified in breast cancer 1 (AIB1) survival. Gain of function somatic mutations in stimulates Nrf2 activation in cholangiocarcinoma NFE2L2 gene which lead to disruption of the Nrf2- cells inducing tumour proliferation and Keap1 binding interface complex result in chemoresistance. upregulation of Nrf2 activity. These mutations have Thus, AIB1 has been proposed as a Nrf2 coactivator. been identified in NSCLC, oesophageal squamous In summary, the upregulation of Nrf2 has cell carcinoma, malignant melanoma, skin squamous antioxidant as well as cytoprotective effect in cancer cell carcinoma, head and neck carcinoma and cells. Especially, cytoprotective activity of Nrf2 can cervical cancer. be exploited by cancer cells not only to face their In addition, it has been reported that an indirect way oxidant tumour microenvironment, but also confer of upregulation of Nrf2 activity is the loss of function chemo- or/and radio- resistance during anticancer KEAP1 somatic mutations. These mutations have therapies. Consequently, suppression of Nrf2 been detected in various types of cancer [lung cancer activity in cancer cells inhibits tumour growth and (NSCLC), thyroid papillary cancer, oesophageal enhances the efficacy of chemotherapeutic agents. cancer, gastric adenocarcinoma, hepatocellular and Therefore, Nrf2 could be a target not only for cancer cholangiocellular carcinoma, gallbladder cancer, chemoprevention (via activating compounds) but colorectal adenocarcinoma, caecum carcinoma, also for cancer treatment (via inhibitors) (Shibata et breast ductal carcinoma and adenocarcinoma, al., 2008a; Shibata T. et al, 2008b; Wang et al., 2008; endometrial adenocarcinoma, ovarian serous cancer Chen et al., 2010; Solis et al., 2010; Yoo et al., 2010; and epithelial cancer, prostate adenocarcinoma, Kim et al., 2010; Shibata et al., 2010; Wang et al., kidney and urinary tract cancer, malignant 2010; Muscarella et al., 2011; Shibata et al., 2011; melanoma and neuroblastoma]. Chen Q et al., 2012; Guo et al., 2012; Hanada et al., Another mechanism of constitutive activation of 2012; Hu et al., 2012; Kim et al., 2012; Liao et al., Nrf2 in cancer cells is the silence of KEAP1 gene 2012; Sporn and Liby, 2012; Yamadori et al., 2012; caused by hypermethylation of KEAP1 gene Barbano et al., 2013; Gañán-Gómez et al., promoter. This silencing mechanism of KEAP1 gene 2013; Martinez et al., 2013; Shelton and Jaiswal, has been detected in human lung cancer tissue cells 2013; Shin et al., 2013; Ziros et al., 2013; Zhang et (squamous, adenocarcinoma, al., 2013; Funes et al., 2014; Gorrini et al., 2014; Ji adenosquamous), lung cancer cell lines, human et al., 2014; Onodera et al., 2014; Schultz et al., breast cancer tissues, colorectal cell lines, prostate 2014). cancer cell lines, human malignant gliomas and
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Exogenous Nrf2 inducers.
Disease LPS (lipo-polysaccharide)-induced septic shock in Lung cancer, thyroid cancer, ovarian cancer, breast Nrf2 KO mice results in premature mortality in cancer, prostate cancer, endometrial cancer, cervical comparison with wild type mice, and non-lethal cancer, gastric cancer, oesophagus cancer, colorectal exposure to LPS results in greater lung inflammation cancer, gallbladder cancer, liver cancer, skin cancer, and injury in Nrf2 KO mice. acute myeloid leukemia. Regarding asthma disease, it has been observed that the disruption of Nrf2 can cause severe airway Airway diseases inflammation and airway hyper-responsiveness in Oxidative stress has been associated with the mouse models of asthma. pathogenesis of many acute and chronic airway IPF is a fibroproliferative disease thought to be disorders. triggered by repeated alveolar epithelial cell injury. ALI and its severe form ARDS are characterised by Rodent models of bleomycin-induced lung fibrosis severe systemic hypoxemia in seriously ill patients. have been used to study IPF. The pulmonary Hypoxemia is associated with production of fibrogenic effects of bleomycin are antagonised by excessive ROS, and thus oxidative stress is a major antioxidant enzymes like SODs in rodents. contributor to the pathogenesis of ALI. In such Moreover, it has been noticed that Nrf2 KO mice hypoxic situations oxygen is one of the most treated with bleomycin had elevated levels of TGF- commonly used supplemental therapeutic agents. β, the main fibrogenic factor. However, oxygen supplementation-induced Finally, it has been reported that Nrf2 has a hyperoxia can also cause lung injury and airway protective role against airway infection by RSV in inflammation. Nrf2 has been proposed as a mice (Reddy, 2008; Cho and Kleeberger, 2010). hyperoxia susceptibility gene that modulates ALI in Disease vivo. Acute lung injury (ALI), emphysema/chronic Emphysema is characterised by loss of pulmonary obstructive pulmonary disease (COPD), lung elasticity as a result of permanent alveolar wall disorder during sepsis [LPS (lipo-polysaccharide)- destruction and represents the alveolar lesion in induced septic shock], asthma/allergic airway COPD. Cigarette smoke is a major contributor to diseases, idiopathic pulmonary fibrosis (IPF), viral emphysema and COPD pathogenesis. Chronic airway disease (RSV - respiratory syncytial virus) exposure to cigarette smoke in Nrf2 knockout (KO) mice causes more severe emphysema than in wild Cardiovascular disease type mice. This is associated with greater levels of Nrf2 is expressed in the cardiovascular system (heart inflammation, oxidative stress and endothelial and and blood vessels), and Nrf2 signaling is implicated epithelial cell apoptosis in the Nrf2 KO mice. in the regulation of vascular homeostasis and in the
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prevention of cardiac hypertrophy and heart failure diseases (Crohn's disease and ulcerative colitis), via suppression of oxidative stress. Although Nrf2 chemical carcinogenesis in the gastrointestinal has been proposed as a therapeutic target in system cardiovascular diseases like atherosclerosis, there is Neurodegenerative diseases some evidence that reveal the role of Nrf2 as pro- atherogenic factor via a different mechanism. Oxidative stress is involved in the pathogenesis of a Nevertheless, modulation of Nrf2 has been wide range of chronic neurodegenerative diseases supported for the prevention and the treatment of such as AD, PD and HD. heart diseases (Sussan et al., 2008; Koenitzer and AD is characterised by increased accumulation in the Freeman, 2010; Freigang et al., 2011). brain of neurotoxic and oxidative elements such as iron. In addition, increased oxidative damage of Diabetes, diabetic nephropathy, proteins and lipid peroxidation has been detected in diabetic neuropathy the brain of AD patients. Reactive astrocytes and Nrf2-mediated expression of endogenous activated microglia contribute to the oxidative stress cytoprotective enzymes and other antioxidant observed in AD brain. The expression profile of Nrf2 molecules has been shown to be an adaptive defence and ARE-regulated proteins in AD brain tissue mechanism against high glucose-induced oxidative supports the hypothesis that Nrf2 signalling may be damage in diabetes. Diabetic nephropathy and involved in the early stages of AD. neuropathy have been studied in correlation with the PD, the second most common neurodegenerative activity of Nrf2 pathway, and it has been found that disease after AD, is characterised by the preferential Nrf2 exerts a protective role against these long-term loss of dopaminergic neurons in the substantia nigra. complications of diabetes (Jiang et al., 2010; Cheng Mitochondrial dysfunction and neuroinflammation et al., 2011; Negi et al., 2011). in PD play a crucial role in PD pathogenesis and the subsequent oxidative stress has been suggested to be Obesity/metabolic syndrome responsible for the degeneration of nigral While it appears that the Nrf2 pathway is a regulator dopaminergic neurons. Nrf2 pathway may have a of energy metabolism, its precise effects and the neuroprotective effect on PD and its activation may underlying mechanisms are still controversial. In be a novel therapeutic approach. some contexts Nrf2 is protective and high-fat diet- HD is a rare neurodegenerative disorder inherited in induced obesity, while in others it is a contributing an autosomal dominant manner. Work in mouse factor to metabolic disease. Nrf2 can induce several model has shown that Nrf2 can have neuroprotective metabolic regulators in adipose tissue and liver such roles against HD and might be a novel treatment as PPARγ, C/EBPβ and AhR, and it can repress target for HD. Furthermore, it has been reported that others such as FGF21. The exact mechanisms by Nrf2 can also potentially protect from neuronal which Nrf2 cross-talks with these factors are the damage in other neurological diseases such as ALS, focus of ongoing research (Chartoumpekis and Freidrich's ataxia, Down syndrome, multiple Kensler, 2013). sclerosis, traumatic brain injury and cerebral Liver and gastrointestinal diseases haemorrhages (Ramsey et al., 2007; Calabrese et al., 2008; de Vries et al., 2008; Jazwa et al., 2011; Nrf2 has been demonstrated to be a key factor Tufekci et al., 2011). dictating susceptibility to oxidative and chemical- induced injury in the gastrointestinal system. In vivo Disease experiments have revealed that Nrf2 KO mice are Alzheimer's disease (AD), Parkinson's disease (PD), more susceptible to acetaminophen-induced Huntington's disease(HD), Freidrich's ataxia, hepatocellular injury, benzo(a)pyrene-induced amyotrophic lateral sclerosis (ALS), multiple tumour formation, and Fas- and TNFα-mediated sclerosis, Down syndrome, traumatic brain injury, hepatocellular apoptosis. In addition, Nrf2 may be cerebral haemorrhage important in protecting against liver fibrosis and Rheumatoid arthritis gallstone development. Regarding intestinal ROS play an important role in the pathogenesis of diseases, it has been suggested that Nrf2 plays an rheumatoid arthritis (RA), and antioxidant important role in the maintenance of intestinal substances and enzymes reduce cartilage damage in integrity and may serve as novel target for therapies animal models of RA. It has been reported that a to prevent or treat Crohn's disease or ulcerative deficiency in Nrf2-mediated antioxidant defences colitis (Aleksunes and Manautou, 2007). plays a central role in pathogenesis of RA. Oxidative Disease stress is one of the factors that contribute to RA, and Drug-induced hepatotoxicity, hepatocellular Nrf2 could play an important role in alleviating its apoptosis, liver fibrosis, gallstone disease, bowel effects (Wruck et al., 2011).
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Uveitis Aging Uveitis is an inflammatory eye disease that can cause A popular "hypothesis" about the causes of aging is blindness. the "free radical theory", which considers aging as The main characteristic of uveitis is an inappropriate the result of progressive damage to macromolecules innate immune response resulting in local tissue and cellular structures caused by exposure to injury. endogenous and exogenous pro-oxidant substances, ROS production with secretion of inflammatory notably free radicals. Nrf2 and its homologues in cytokines and leukocytes infiltration has been invertebrate models of aging have been shown to documented in a model of LPS-induced uveitis. exert anti-aging and pro-longevity functions. In this model, due to an inadequate activation of Nevertheless, Nrf2 activity generally declines with Nrf2, the induction of antioxidant and anti- age, and this decline is associated with decreased inflammatory responses is also incomplete. expression and/or inducibility of antioxidant genes. Potentiation of the antioxidant response with an Overall, it is believed that, if properly fine-tuned, the Nrf2-inducing compound led to increased enzyme Nrf2 pathway can have life span-extending effects, expression of protective enzymes, reduced cytokine and can therefore be a target for promoting longevity expression, and decreased leukocyte adhension, and extending the disease-free period of life (the suggesting Nrf2 as a potential therapeutic target in "health span") (Sykiotis and Bohmann, 2010). uveitis (Nagai, 2009).
Genes positively regulated by Nrf2 in humans.
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Cancer Res. 2013 May 15;73(10):3097-108 Yoo NJ, Kim HR, Kim YR, An CH, Lee SH. Somatic mutations of the KEAP1 gene in common solid cancers. Zhang C, Su ZY, Khor TO, Shu L, Kong AN. Sulforaphane Histopathology. 2012 May;60(6):943-52 enhances Nrf2 expression in prostate cancer TRAMP C1 cells through epigenetic regulation. Biochem Pharmacol. Barbano R, Muscarella LA, Pasculli B, Valori VM, Fontana 2013 May 1;85(9):1398-404 A, Coco M, la Torre A, Balsamo T, Poeta ML, Marangi GF, Maiello E, Castelvetere M, Pellegrini F, Murgo R, Fazio VM, Ziros PG, Manolakou SD, Habeos IG, Lilis I, Chartoumpekis Parrella P. Aberrant Keap1 methylation in breast cancer and DV, Koika V, Soares P, Kyriazopoulou VE, Scopa CD, association with clinicopathological features. Epigenetics. Papachristou DJ, Sykiotis GP. Nrf2 is commonly activated 2013 Jan;8(1):105-12 in papillary thyroid carcinoma, and it controls antioxidant transcriptional responses and viability of cancer cells. J Clin Chartoumpekis DV, Kensler TW. New player on an old field; Endocrinol Metab. 2013 Aug;98(8):E1422-7 the keap1/Nrf2 pathway as a target for treatment of type 2 diabetes and metabolic syndrome. Curr Diabetes Rev. 2013 Figarska SM, Vonk JM, Boezen HM. NFE2L2 Mar 1;9(2):137-45 polymorphisms, mortality, and metabolism in the general population. Physiol Genomics. 2014 Jun 15;46(12):411-7 Cheng X, Ku CH, Siow RC. Regulation of the Nrf2 antioxidant pathway by microRNAs: New players in Funes JM, Henderson S, Kaufman R, Flanagan JM, Robson micromanaging redox homeostasis. Free Radic Biol Med. M, Pedley B, Moncada S, Boshoff C. Oncogenic 2013 Sep;64:4-11 transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer Cho HY. Genomic structure and variation of nuclear factor survival. Mol Cancer. 2014 Feb 3;13:20 (erythroid-derived 2)-like 2. Oxid Med Cell Longev. 2013;2013:286524 Gorrini C, Gang BP, Bassi C, Wakeham A, Baniasadi SP, Hao Z, Li WY, Cescon DW, Li YT, Molyneux S, Penrod N, Chowdhry S, Zhang Y, McMahon M, Sutherland C, Lupien M, Schmidt EE, Stambolic V, Gauthier ML, Mak TW. Cuadrado A, Hayes JD. Nrf2 is controlled by two distinct β- Estrogen controls the survival of BRCA1-deficient TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene. 2013 Aug cells via a PI3K-NRF2-regulated pathway. Proc Natl Acad 8;32(32):3765-81 Sci U S A. 2014 Mar 25;111(12):4472-7 Gañán-Gómez I, Wei Y, Yang H, Boyano-Adánez MC, Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory García-Manero G. Oncogenic functions of the transcription network provides an interface between redox and factor Nrf2. Free Radic Biol Med. 2013 Dec;65:750-64 intermediary metabolism. 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Namani A, Li Y, Wang XJ, Tang X. Modulation of NRF2 Schultz MA, Hagan SS, Datta A, Zhang Y, Freeman ML, signaling pathway by nuclear receptors: implications for Sikka SC, Abdel-Mageed AB, Mondal D. Nrf1 and Nrf2 cancer. Biochim Biophys Acta. 2014 Sep;1843(9):1875-85 transcription factors regulate androgen receptor transactivation in prostate cancer cells. PLoS One. Onodera Y, Motohashi H, Takagi K, Miki Y, Shibahara Y, 2014;9(1):e87204 Watanabe M, Ishida T, Hirakawa H, Sasano H, Yamamoto M, Suzuki T. NRF2 immunolocalization in human breast This article should be referenced as such: cancer patients as a prognostic factor. Endocr Relat Cancer. 2014 Apr;21(2):241-52 Manolakou SD, Ziros PG, Sykiotis GP. NFE2L2 (nuclear factor, erythroid 2-like 2). Atlas Genet Cytogenet Oncol Shimoyama Y, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T. Haematol. 2015; 19(8):503-521. Polymorphism of Nrf2, an antioxidative gene, is associated with blood pressure and cardiovascular mortality in hemodialysis patients. Int J Med Sci. 2014;11(7):726-31
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OPEN ACCESS JOURNAL INIST-CNRS
Gene Section Review
NR5A1 (nuclear receptor subfamily 5, group A, member 1) Carmen Ruggiero, Mabrouka Doghman, Enzo Lalli Institut de Pharmacologie Moleculaire et Cellulaire CNRS, Valbonne 06560, France (CR), Associated International Laboratory (LIA) NEOGENEX CNRS, Valbonne 06560, France (MD), University of Nice-Sophia-Antipolis, Valbonne 06560, France (EL)
Published in Atlas Database: September 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/NR5A1ID45858ch9q33.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62260/09-2014-NR5A1ID45858ch9q33.pdf DOI: 10.4267/2042/62260 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract DNA/RNA Review on NR5A1, with data on DNA/RNA, on the In 1992 the mouse Sf-1 gene (Nr5a1) was cloned protein encoded and where the gene is implicated. from an adrenal cDNA library using a probe corresponding to the DNA-binding domain (DBD) Identity of the related orphan receptor retinoid X receptor Other names: AD4BP, ELP, FTZ1, FTZF1, POF7, (Lala et al., 1992). SF-1, SF1, SPGF8, SRXY3 Later, its bovine homologue (called adrenal 4- HGNC (Hugo): NR5A1 binding protein, Ad4BP) was identified from an adrenal cDNA library exploiting the partial sequence Location: 9q33.3 of a protein purified from bovine adrenal extracts Note: Steroidogenic factor-1 (SF-1) is an orphan (Honda et al., 1993). The proteins encoded by both member of the nuclear receptor superfamily which these murine and bovine cDNAs were able to acts as a key regulator of adrenogonadal activate promoters of steroid hydroxylase enzymes, development and tissue-specific gene expression in indicating that a common steroidogenic factor had steroidogenic cells. Parker's and Morohashi's groups been identified. Initially the mouse gene encoding identified SF-1 by its capacity to activate SF-1 was called FtzF1, similar to the Drosophila transcription from multiple P450 steroidogenic orphan nuclear receptor fushi tarazu factor homolog enzyme promoters (Lala et al., 1992; Morohashi et 1 (FTZ-F1) and mapped to chromosome 2 (Ueda et al., 1992). Besides its recognized role as a master al., 1990; Swift and Ashworth, 1995; Taketo et al., regulator of steroidogenesis in the adrenal cortex and 1995). gonads, recent studies indicate that the regulation of The corresponding human SF-1 gene was initially gene expression in the adrenal cortex by SF-1 also termed FTZF1 and later NR5A1 (see above) involves processes other than steroidogenesis according to the standard nomenclature system for (reviewed in Lalli et al., 2013). nuclear receptors.
Figure 1. NR5A1 chromosomal localization. The NR5A1 gene maps on chromosome 9q33.3 (adapted from GeneCards).
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Figure 2. Structure of the SF-1 protein. SF-1 contains the major structural features present in all nuclear receptors. N, N- terminus of the protein; DBD, DNA binding domain with two zinc finger (ZnI and ZnII) motifs; Ftz-F1, Fushi-tarazu-F1 domain with a nuclear localization signal (NLS); Hinge, hinge region displaying a Pro-rich (proline-rich) region and an AF-1- (transcriptional activation domain 1) like domain; LBD, ligand-binding domain; AF-2, transcriptional activation domain 2; C, C-terminus of the protein.
Description helix may also serve as a platform for coactivators and other DNA-bound factors interaction (Little et Size: 26.18 Kb (GeneCards), 7 exons. mRNA: 3095 al., 2006). bp (NM_004959). The hinge region, which lies between the N-terminal Transcription DBD and the C-terminal LBD is more than a flexible The human NR5A1 gene is mapped to the long arm connector between the LBD and the DBD. It of chromosome 9 (9q33, Figure 1) and consists of 7 participates in conjunction with helix 1 (H1, see exons spanning approximately 27 Kb of genomic below) to promote an active protein conformation DNA (Taketo et al., 1995; Oba et al., 1996; Wong et (Desclozeaux et al., 2002). Furthermore, it is al., 1996). Exon 1 is untranslated. important for post-transcriptional/translational modifications, like phosphorylation and Protein SUMOylation (Hammer et al., 1999; Komatsu et al., 2004; Lee et al., 2005; Lewis et al., 2008). In Description particular, phosphorylation of the hinge region The SF-1 protein contains the typical domains of enhances SF-1 overall stability and transcriptional other members of the nuclear receptor superfamily ( activity (Desclozeaux et al., 2002). NURSA): an N-terminal DBD including two zinc The LBD contains 12 helices (H1-H12, like other fingers, a flexible proline-rich hinge region nuclear receptors), that can form an AF2 domain for displaying AF-1 - like activation activity, a ligand the recruitment of cofactors. SF-1 has been binding domain (LBD) and a C-terminal AF-2 considered as an "orphan" nuclear receptor for many activation domain, which is required for years because of the absence of high-affinity transcriptional activity and cofactor interactions naturally occurring ligands identified. This led to the (Figure 2). hypothesis that the LBD of SF-1 could adopt a stable A proximal (P) box implicated in the specific conformation in the absence of ligand (Desclozeaux recognition of DNA target sequences by nuclear et al., 2002). Later, different groups have been able receptors has been described in the first zinc finger to crystallize the SF-1 LBD, showing that small of SF-1 DBD. This sequence interacts with the phospholipids ligands (e.g. phosphatidylinositols) hormone response element core in the major groove can bind to this domain (Krylova et al., 2005; Li et of the DNA helix by recognizing variations on the al., 2005; Wang et al., 2005). AGGTCA motif (Evans, 1998). SF-1 also exhibits a Protein translation: FTZ-F1 box or A box, which represents a 30- MDYSYDEDLD ELCPVCGDKV SGYHYGLLTC aminoacid extension of the DBD, being important ESCKGFFKRT VQNNKHYTCT ESQSCKIDKT for DNA anchoring. Indeed, at variance from most QRKRCPFCRF QKCLTVGMRL nuclear receptors, SF-1 binds to target genes EAVRADRMRG GRNKFGPMYK monomerically rather than as a homo- or RDRALKQQKK AQIRANGFKL ETGPPMGVPP heterodimer and with highest affinity to PPPPAPDYVL PPSLHGPEPK GLAAGPPAGP 5'YCAAGGYCR'3 (where Y= T/C; R= G/A) (Ueda LGDFGAPALP MAVPGAHGPL AGYLYPAFPG and Hirose, 1991; Wilson et al., 1993). X-ray RAIKSEYPEP YASPPQPGLP YGYPEPFSGG crystallography of the SF-1 DBD complexed with a PNVPELILQL LQLEPDEDQV RARILGCLQE sequence in the inhibin-α gene proximal promoter PTKSRPDQPA AFGLLCRMAD QTFISIVDWA region has shown that the A-box primarily interacts RRCMVFKELE VADQMTLLQN with the 5' flanking sequence and the first part of the CWSELLVFDH IYRQVQHGKE GSILLVTGQE half site in the minor groove of DNA (Ito et al., VELTTVATQA GSLLHSLVLR AQELVLQLLA 2000a; Little et al., 2006). Moreover, the same study LQLDRQEFVC LKFIILFSLD LKFLNNHILV revealed that SF-1 displays a helix in the C-terminal KDAQEKANAA LLDYTLCHYP segment of the FTZ-F1 box which interacts with HCGDKFQQLL LCLVEVRALS both the core DBD and the DNA, thus acting as an MQAKEYLYHK HLGNEMPRNN important determinant of the complex stability LLIEMLQAKQ T (Little et al., 2006). It has been proposed that this
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Sequence length: 461 aa; Molecular weight: 51,636 whereas WT1 plays a role as a positive regulator of kDa SF-1 expression in the developing gonad (Wilhelm Expression and Englert, 2002), like the LIM homeobox gene Lhx9 (Birk et al., 2000). Interestingly, genetic and SF-1 localization in adult tissues has been widely molecular evidence shows that the transcription co- investigated in mice, rats, human and other factor CITED2 interacts with WT1 to promote SF-1 vertebrates. Its expression pattern is consistent with expression in the AGP before the separation between its role as a steroidogenesis master regulator and is gonad and adrenal cortex, a critical time during strikingly overlapping with that of another nuclear embryogenesis (Val et al., 2007). receptor, Dax-1 (Nr0b1) (Ikeda et al., 1996; Swain et Recently, Morohashi and collaborators have al., 1996; Tamai et al., 1996; Ikeda et al., 2001), identified one intergenic and three intragenic which functions as a negative regulator of SF-1 (intronic) enhancers, which are essential for tissue activity. SF-1 is expressed in tissues involved in and SF-1 stage specific expression in mice. Those steroid hormone production and reproductive tissue-specific enhancers direct SF-1 expression to function, i.e. the three layers of the adrenal cortex, the fetal adrenal (Fetal Adrenal Enhancer, fAdE, testicular Leydig and Sertoli cells, ovarian localized to intron 4) (Zubair et al., 2006), the interstitium, theca and granulosa cells, and, to a developing pituitary and adult gonadotropes lesser degree, corpus luteum (Honda et al., 1993; (Pituitary Gonadotrope Enhancer, PGE, localized to Ikeda et al., 1993; Morohashi et al., 1994; Ramayya intron 6) (Shima et al., 2008), the developing et al., 1997; Morohashi, 1999). SF-1 is also diencephalon and adult VMH (VMH Enhancer, expressed in non-steroidogenic tissues like pituitary VMHE, localized to intron 6, upstream of PGE) gonadotropes. It is also expressed in the dorsomedial (Shima et al., 2005) and fetal Leyding cells (Fetal portion of the ventromedial hypothalamus (VMH) Leydig cell Enhancer, FLE; intergenic, located (Ikeda et al., 1994; Shinoda et al., 1995), in the upstream of the transcriptional start site) (Shima et endothelial linings of the venous sinuses and pulp al., 2012). Although the activity of these enhancers veins in the spleen (Ramayya et al., 1997; Morohashi has been established only in mice, all enhancers, like et al., 1999), and in a subset of hippocampal neurons. the basal promoter, are conserved among the It has been described that in developing human different animal species (Shima et al., 2012). embryos SF-1 represents the earliest marker of adrenogonadal differentiation, first appearing in the Localisation urogenital ridge (Ikeda et al., 1994; Morohashi et al., SF-1 is constitutively localized in the nucleus where 1995; Hanley et al., 1999; Hanley et al., 2001). it acts as a DNA-binding transcription factor. In the mouse, SF-1 is first expressed at embryonic Interestingly, it has been described that it also moves day 9 (E9.0) in the adrenal/gonadal primordium inside the nucleus according to the status of its post- (AGP) (Hatano et al., 1996). After gonadal and translational modifications (Chen et al., 2004; Fan et adrenal anlagen separation at E11.0, SF-1 is al., 2004). SUMOylation seems to repress SF-1 expressed throughout gestation in the developing activity as the mutations of its SUMO acceptor sites steroidogenic adrenal portion and in zona K119 and K194 enhance SF-1 - driven gene glomerulosa, fasciculata and reticularis of the adult activation. It has been proposed that SUMO- gland. In contrast, it is not expressed in the neural conjugated SF-1 localizes to the PML nuclear crest cells that migrate to the medulla during speckles, where SF-1 is sequestered from development (Ikeda et al., 1994) nor in the adult nucleoplasm and is associated with repressors, like medulla (Ikeda et al., 1993). While SF-1 is expressed DP103 (Lee et al., 2005; Wang et al., 2013). SF-1 in the indifferent gonad, it displays a sexually can also be acetylated at the KQQKK sequence in dimorphic expression pattern in the developing testis the Ftz-F1 box and activated by the histone and ovaries (Ikeda et al., 1994). Indeed, it disappears acetyltransferase p300 (Chen et al., 2005). from the ovaries between E13.5 to E16.5 and Following cAMP stimulation, SF-1 spreads out into reappears at the beginning of folliculogenesis, being discrete transcriptionally active foci containing RNA expressed in granulosa, thecal and luteal cells of the polymerase II, p300 (Chen et al., 2005) and the adult ovary (see above, Ikeda et al., 1993; Hanley et ubiquitous histone acetyltransferase GCN5 (Fan et al., 1999; Hanley et al., 2001). al., 2004). It has been hypothesised that SF-1 is During embryonic development, SF-1 expression is recruited to those transcriptionally active loci as a tightly temporally and spatially controlled. An E- result of physical interactions with co-regulators like box-binding site within the basal promoter of SF-1 p300 and GCN5. Furthermore, when SF-1 is gene has been described to be critical for SF-1 acetylated by p300 at the FTZ-F1 domain, its expression (Nomura et al., 1995). The transcription binding to p300 increases. It seems that acetylation factor POD1/capsulin has been reported to repress is involved in retaining SF-1 in the transcriptionally SF-1 expression in the gonad through binding to this active nuclear foci, thus promoting SF-1 - mediated E-box (Tamura et al., 2001; Cui et al., 2004), target gene transcription (Chen et al., 2005). Neither
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phosphorylation at Ser 203 (Hammer et al., 1999) similar to those seen with NR5A1 mutations nor ubiquitination (Chen et al., 2007) appear to (reviewed in Lalli, 2003 and Lalli, 2014). change or affect SF-1 distribution. Recently, it has Putative phospholipid ligands, post-translational been shown that SF-1 is also located in the modifications (phosphorylation, sumoylation, centrosome. Immunofluorescence analysis revealed acetylation), epigenetic gene expression regulation that it colocalizes with the centrosome marker γ- and gene dosage (see below) can influence SF-1 tubulin in mouse adrenocortical Y1 and mouse transcriptional activity, subnuclear localization testicular Leydig MA-10 cells (Lai et al., 2011). and/or DNA-binding activity (reviewed in Hoivik et Sucrose gradient fractionation studies in Y1 cells al., 2010; Lalli, 2010; Schimmer and White, 2010). have confirmed immunofluorescence results (Lai et By different genomic approaches, multiple levels of al., 2011). A centrosome localization signal (CLS) regulation exerted by SF-1 dosage on transcriptome, has also been identified by deletion analysis and and more recently on its cistrome have been explored localized to aa 348-367 (Lai et al., 2011). Moreover, (Doghman et al., 2007; Doghman et al., 2013). These SF-1 centrosomal localization results to be recent studies have shown that SF-1 regulates independent from microtubule (MT) transportation, distinct categories of genes in adrenocortical cancer as after MT depolymerization SF-1 still colocalizes cells according to its dosage. Moreover, the binding with acetylated tubulin (Wang et al., 2013). of SF-1 to chromatin sites in condition of different SF-1 dosage correlates with differential regulation of Function gene expression (Doghman et al., 2013). SF-1 as a master regulator of gene expression in Transcriptional profiling revealed that SF-1 dosage- steroidogenic cells dependent genes are involved in lipid and steroid SF-1 was identified as a key factor that regulates the metabolism, but also in apoptosis, cell cycle expression of several steroidogenic enzymes in a regulation, cell adhesion and transcriptional tissue-specific manner (Lala et al., 1992; Morohashi regulation (reviewed in Lalli et al., 2013). Other et al., 1992). In steroidogenic tissues, SF-1 regulates recent studies show that SF-1 knockdown affects the steroidogenic pathways including genes encoding expression of a large number of transcripts that are cytochrome P450 enzymes as CYP11A1 (Chau et not only involved in steroid synthesis (Schimmer et al., 1997), CYP17A1 (Bakke et al., 1995), al., 2011). A recent study suggested that SF-1 may CYP21A2, CYP11B1 (Morohashi et al., 1993), be involved in glucose metabolism by regulating CYP11B2 (Bassett et al., 2002), 3β-hydroxysteroid genes of the glycolytic pathways (Baba et al., 2014) dehydrogenase (3βHSD) (Leers-Sucheta et al., even if this was not observed in other studies 1997), steroidogenic acute regulatory protein (StAR) (Schimmer et al., 2011; Doghman et al., 2013). (Sugawara et al., 1996). Other evidence shows that From Knock-out mice models to human SF-1 regulates many genes involved in development mutations phenotype: Evidence of the key role of and steroidogenic function (reviewed in Schimmer SF-1 in differentiation and development. and White, 2010). SF-1 is generally considered as an Studies of both complete and tissue-specific activator of gene expression, but it can act as a knockout mice have demonstrated that SF-1 is a key negative regulator of the type 4 adenylyl cyclase and factor for the development of the adrenal glands, of CYP11B2 (Rui et al., 2008; Ye et al., 2009). SF- gonads, ventromedial hypothalamus and in pituitary 1 also regulates genes involved in sex determination gonadotropes functions (Luo et al., 1994; Sadovsky and development of reproductive tissues including et al., 1995; Shinoda et al., 1995; Ikeda et al., 1995; DAX1, AMH, SOX9, SRY (Kawabe et al., 1999; De Zhao et al., 2001). To characterize the role of SF-1 Santa Barbara et al., 1998; De Santa Barbara et in different tissues and to distinguish between the al.,2001; Sekido et al., 2008). Thus, SF-1 plays a direct and secondary effects of SF-1 deficiency, central role in development and function of the Keith Parker's laboratory developed mice models steroidogenic and reproductive systems. that are specifically deleted for Sf-1 in gonadotrope Some SF-1-interacting proteins (positive and cells, gonads and VMH by using the Cre/lox negative cofactors) are expressed in a tissue-specific approach (Jeyasuria et al., 2004; Pelusi et al., 2008; manner whereas others are more widely expressed. Zhao et al., 2008). Further studies are necessary to better understand Role in adrenal and gonads how these cofactors could contribute to control cell- Sf-1 null mice lack adrenal glands and gonads and and time-specific expression of SF-1-dependent die from adrenal insufficiency within the first week genes. Interactions between SF-1 and DAX-1 after birth. Mice lacking Sf-1 show early adrenal and represent a particular interest (Ikeda et al., 1996). gonadal development that regresses by apoptosis DAX1, an X-linked gene that encodes a repressor of between E11.5 and E12.5 (Luo et al., 1994; steroidogenic gene expression, modulates the Sadovsky et al., 1995) indicating that Sf-1 is activity of SF-1 (Lalli et al., 1998). Mutations in essential for early development and maintenance of DAX-1 cause X-linked adrenal hypoplasia congenita adrenal and gonadal primordia. and hypogonadotrophic hypogonadism, phenotypes
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SF-1 knockout mice exhibited male-to-female sex gonadotropes can express putative SF-1 target genes reversal of their internal and external genitalia. Since in the absence of SF-1 (Ikeda et al., 1995). their gonads regressed before male sexual The pituitary-specific Sf-1 KO mice have markedly differentiation normally occurs, the internal and decreased levels of LH and FSH and exhibit external urogenital tracts of SF-1 KO mice are hypoplastic gonads, impaired secondary sexual female irrespective of genetic sex. Absence of testes development and are sterile. Administration of in homozygous mutant male mice precludes MIS gonadotropins partially rescues the gonadal (Müllerian inhibiting substance) and androgen phenotype. All these studies establish a primary role production, which accounts for the observed for SF-1 in gonadotrope function in the pituitary in phenotypes (Luo et al., 1994; Sadovsky et al., 1995). mice (Zhao et al., 2001). Heterozygous Sf-1 null mice have decreased adrenal In the brain of SF-1 KO mice, the region of the volume associated with impaired corticosterone ventromedial hypothalamus is disorganized and does production in response to stress and present smaller not show its characteristic structures. The VMH is a testes (Bland et al., 2000). These mice also present a hypothalamic region linked to feeding and appetite defect in compensatory growth in the remaining regulation and female reproductive behavior adrenal following unilateral adrenalectomy, (Shinoda et al., 1995; Ikeda et al., 1995; Zhao et al., indicating that SF-1 is required for cell proliferation 2001). SF-1 is the only gene that is specifically and in steroidogenic tissue (Beuschlein et al., 2002). exclusively expressed in the VMH. It is noteworthy Differences in adrenal development between that SF-1 KO mice that are maintained alive by heterozygous animals and their wild-type littermates adrenal transplantation exhibit late onset obesity were more evident during embryonic development suggesting a potential role of SF-1 in regulation of than postnatally due to a partial compensation of food intake (Majdic et al., 2002). adrenal function after birth (Bland et al., 2004). The nestin promoter, which is active in the CNS, was Thus, a difference between the capacity of the used to create a brain-specific Sf-1 KO micenCre; F/- adrenal gland and gonad to compensate for partial model equivalent of a VMH-specific knockout loss of SF-1 function might be one of the (Zhao et al., 2008). The organization of VMH mechanisms explaining why the gonadal phenotype neurons is dramatically changed in this model, and is more marked than the adrenal phenotype in mice also present an increased anxiety-like behavior humans with heterozygous NR5A1 mutations (see and a decreased locomotor activity (Zhao et al., Implications in pathology). 2008). Moreover, Sf-1 KOnCre; F/- female mice have Male gonad-specific Sf-1 KO mice display impaired follicle development, fertility and sexual hypoplastic testes observed starting from early behaviors and normal body weight, delineating an developmental stages associated with an impaired important role for SF-1 expressed in the VMH in spermatogenesis which makes the animals sterile. female reproductive function, independently of Moreover, in this model, the testes do not descend energy balance regulation (Kim et al., 2010). To (cryptorchidism), demonstrating an in vivo distinguish between the direct metabolic roles of SF- important role of SF-1 in hormonal production for 1 and its developmental side effects, an alternative virilization and testes descent (Jeyasuria et al., mouse model named postnatal VMH-specific SF-1 2004). Sf-1 KO ovaries were indistinguishable from KO was generated in which SF-1 is specifically wild-type during embryogenesis and at birth, but deleted after completion of VMH development using adult females were sterile. In the ovaries, the total CamKII-Cre, a postnatally expressing Cre line (Kim number of ovarian follicles is decreased and corpora et al., 2011). These postnatal VMH-specific Sf-1 KO lutea are lacking, indicating an important role for SF- animals display a diet-induced obesity and revealed 1 in ovulation (Jeyasuria et al., 2004). SF-1 is then that SF-1 is required for normal energy homeostasis essential for normal gonadal function in both male by modulating energy expenditure especially in and female mice. high-fat diet condition (Kim et al., 2010). Although Role in anterior pituitary, VMH and spleen SF-1-expressing neurons do not represent all The consequences of SF-1 KO at the level of neurons within the VMH, many studies establish that pituitary and hypothalamus have important impacts SF-1 neurons in the VMH are on their target organs. Indeed, the pituitaries of SF1 essential for normal energy homeostasis, particularly knockout mice have markedly decreased expression in regulation of energy expenditure (reviewed in of both pituitary gonadotropins [luteinizing hormone Choi et al., 2013). (LH) and follicle-stimulating hormone (FSH)] and It has been shown that disruption of SF-1 also causes have impaired expression of many target genes that developmental abnormalities in spleen tubular regulate gonadal steroidogenesis (Ingraham et al., structure and impaired clearance by the splenic 1994; Shinoda et al., 1995). However, GnRH vascular system (Morohashi et al., 1999). Similar treatment of SF-1 knockout mice induced pituitary defects have been observed in mice with disruption expression of LH and FSH, indicating that of the mouse polycomb 33 gene (M33) and suggest
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an interaction between M33 and SF-1 in splenic The critical role of SF-1 as a developmental development (Katoh-Fukui et al., 2005). regulator became evident by the analysis of the SF-1 involvement in human disease phenotype of Sf-1 KO mice (see above). The role for Genetic evidence for the essential role of SF-1 in Sf-1 gene dosage in the development of adrenals is endocrine development also comes from studies on demonstrated by the finding that Sf-1 heterozygous human patients. These genetic mutations provide mice have hypoplastic adrenals, with a decreased insights into the function of SF-1 and the corticosterone and increased ACTH plasma levels, mechanisms of XY sex reversal, ovarian anomalies especially after stress (Bland et al., 2000). Also in the and adrenal failure (reviewed in Lin and Achermann, adult mouse Sf-1 dosage is critical for compensatory 2008). adrenal growth following unilateral adrenalectomy More than 70 human SF-1 mutations have been (Beuschlein et al., 2002). described, with most of them found in a The function of SF-1 in the regulation of heterozygous state and only a few found in adrenocortical growth has a particular relevance to homozygote or compound heterozygote state (see understand the mechanisms of adrenocortical Mutation). In humans, the first description of a tumorigenesis. Important input came from pediatric heterozygous loss-of-function SF-1 mutation adrenocortical tumors studies. These tumors are (G35E) was made in a patient with adrenal failure particularly frequent in southern Brazil and are and complete 46,XY sex-reversal, closely matching associated with the presence of the germline R337H the phenotype of Sf-1 null mice (Achermann et al., TP53 mutation, NR5A1 copy number gain/gene 1999). Afterwards, several other patients have been amplification and SF-1 protein overexpression described presenting variable degrees of gonadal and (Ribeiro et al., 2001; Figueiredo et al., 2005; adrenal dysgenesis caused by SF-1 Pianovski et al., 2006; Letouzé et al., 2012). haploinsufficiency, while only one homozygous SF- Subsequent studies involving both a human 1 mutation has been described (R92Q) in a patient adrenocortical cell line with inducible SF-1 with adrenal hypoplasia and 46,XY sex-reversal overexpression and a transgenic mouse model (Achermann et al., 2002). In several cases, SF-1 bearing multiple copies of the Sf-1 gene showed that haploinsufficiency has been shown to be associated an increased SF-1 dosage activates adrenocortical with isolated gonadal dysgenesis or ovarian cell proliferation and induces adrenocortical insufficiency, while only one case has been neoplasia (Karpova et al., 2005; Doghman et al., described of a prepubertal girl with adrenal 2007). Moreover, the transcriptional activation insufficiency and apparently normal ovaries function (AF2 domain) of SF-1 is necessary for its (Biason-Lauber et al., 2000). It appears that a species role in adrenocortical cell proliferation. difference exists in the sensitivity to SF-1 dosage. In Interestingly, those tumors develop in the fact, while adrenals and gonads are both affected by subcapsular region of the Sf-1 transgenic adrenal Sf-1 haploinsufficiency in mice, in humans the great glands and express the gonadal markers Gata4 and majority of heterozygote SF-1 mutations are AMH, derived most probably from undifferentiated associated with disorders of sex development (Lin et adrenogonadal precursors (Looyenga and Hammer, al., 2007), premature ovarian failure (Lourenço et al., 2006). Transcriptome analysis revealed that SF-1 2009) or male infertility (Bashamboo et al., 2010) regulates new and distinct categories of gene rather than adrenal development (see Mutation and involved in multiple functions according to its Implication in pathology). dosage (Doghman et al., 2013) (see above). Recently, novel SF-1 mutations were identified in Altogether, it appears that SF-1 dosage plays an patients with 46,XY DSD and adrenal insufficiency. important role during adrenal development and In vitro analysis revealed that these SF-1 mutations tumorigenesis. affect not only steroidogenesis but also transcription Role of SF-1 in embryonic stem (ES) cells of the BDNF gene that is involved in energy balance differentiation (Malikova et al., 2014). However, in contrast to The role of SF-1 in stem cells differentiation into mice, consequences on weight were not found in steroid-producing cells was first investigated in 1997 humans with SF-1 mutations and further studies are by Crawford and colleagues (Crawford et al., 1997). necessary to confirm the impact of SF-1 on body They reported that the forced expression of SF-1 weight regulation in human. directed mouse ES cells into the steroidogenic cell A recent study describes a clinical phenotype of lineage, although the steroidogenic capacity of these severe 46,XY-DSD with asplenia, caused by a novel cells was very limited. Upon SF-1 transfection, homozygous SF1 mutation (R103Q) suggesting that human mesenchymal stem cells (MSC) were shown SF-1 is required for spleen development in humans to be successfully converted into steroidogenic cell (Zangen et al., 2014). lineage appearing to be glucocorticoid- rather than SF-1 dosage as a key regulator of adrenocortical testosterone-producing cells (Yawaza et al., 2006). growth and of tumorigenesis Moreover, Gondo et al., reported that steroid hormone production was observed for more than 112
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d when bone marrow-derived MSC were infected failure, severe gonadal dysgenesis and persistence of with SF-1 by an adenoviral vector (Gondo et al., Mülleran structures (a phenotype resembling Sf-1 2008). Interestingly introduction of LRH1 (Liver- null knockout mice). The first patient showed a specific receptor, NR5A2), another member of the heterozygous de novo G35E mutation which disrupts NR5A family, resulted in differentiation of human the P-box primary DNA-binding motif within the MSCs into steroidogenic cells (Yawaza et al., 2009). first zinc finger of SF-1 DBD (see Protein In 2011, Yazawa et al., reported a method for description), thus resulting in diminished target gene differentiating mouse ES cells into steroid- binding and transactivation (Achermann et al., 1999; producing cells through tetracycline-controlled Ito et al., 2000a; Tremblay et al., 2003). The second transcriptional activation of SF-1 (Yazawa et al., patient exhibited a homozygous R92Q mutation 2011). within the A-box (see Protein description), resulting It has been demonstrated that human ES/iPS in a variable and partial loss of SF-1 activity (induced Pluripotent Stem) cells can be (Achermann et al., 2002). differentiated into steroid-producing cells by first Other reported mutations were shown to impair inducing them to differentiate into the mesodermal transcriptional activity through abnormal DNA lineage and then introducing SF-1 (Sonoyama et al., binding (V15M, M78I, G19S), perturbed sub- 2012). The steroidogenic cells obtained expressed nuclear localization (V15M, M78I, as well as mRNAs encoding adrenocortical or gonad-specific another mutation in the DBD, C33S, Köhler et al., steroidogenic enzymes and produced a wide variety 2008) or by disrupting the putative ligand-binding of steroid (Sonoyama et al., 2012). All these findings pocket (L437Q) (Lin et al., 2007). Another mutation indicate that SF-1 could work as a differentiating affecting the proximal part of the SF-1 LBD is factor for the steroidogenic differentiation of R255L, a de novo heterozygous change identified in multipotent stem cells and open new perspectives for a girl showing primary adrenal insufficiency at 14 future regenerative therapy. months of age (Biason-Lauber and Schoenle, 2000). The mutant SF-1 protein was shown to be Mutations transcriptionally inactive, but without a dominant negative effect. Studies carried out on human patients provided Further, in-frame deletions and frameshift and genetic evidence for the pivotal role of SF-1 in missense mutations have been detected in four endocrine development. Several SF-1 mutations families with histories of both 46,XY DSD and have been described in humans and are associated 46,XX primary ovarian insufficiency and in 2 of 25 with a wide variety of human reproductive patients with sporadic ovarian insufficiency phenotypes, like 46,XY disorders of sex (Lourenço et al., 2009). Functional studies showed development (DSD), hypospadias, anorchia, male that those mutations substantially impaired SF-1 infertility or primary ovarian insufficiency in women transactivation activity. One of the mutation and adrenal failure (reviewed in Lin and Achermann, identified by Lourenço et al. in the LBD is D293N. 2008; Ferraz-de-Souza et al., 2011; Human Gene The mutated protein partly activated both CYP11A1 Mutation Database). Several of these genetic and CYP19A1 promoters (Lourenço et al., 2009). alterations are represented by heterozygous Homozigosity for D293N caused either 46, XY nonsense or frameshift mutations which alter RNA complete gonadal dysgenesis or 46, XY DSD, stability through nonsense-mediated decay or suggesting a pivotal role of this domain in produce a truncated non-functional protein modulating male sex differentiation. (reviewed in Lin and Achermann, 2008). Other NR5A1 mutations can affect also the hinge region of genetic alterations are present as nucleotide the protein (see Protein structure). The first mutation polymorphisms or deletions. discovered in the hinge region was G146A Several novel heterozygous missense mutations (WuQiang et al., 2003). The mutated protein shows identified provide interesting insights into SF-1 slightly diminished transactivation activity on the structure-function correlation. As described below, CYP11A promoter and the CYP19 promoter II. most of those missense mutations lie within the However, the mutation does not alter protein primary or accessory DBD affecting highly- expression or stability and does not display dominant conserved aminoacid residues (reviewed in Lin and negative effect. Achermann, 2008). These genetic alterations Recent studies in patients with novel NR5A1 interfered with DNA binding and inhibited mutations have shown no clear genotype-structure- transcriptional activation in transient gene function-phenotype correlation (Camats et al., expression assays. 2012). Thus, further investigation is necessary to The earliest studies on NR5A1 mutations were based better understand the broad range of clinical on single case reports (Achermann et al., 1999; manifestations produced by SF-1 mutations. Achermann et al., 2002). They focused on the rare group of 46,XY females exhibiting primary adrenal Implicated in
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SF-1 expression in prostate cancer the phenotype, as shown by low levels of testosterone, inhibin β and AMH and an elevation of Recently, it has been reported that SF1 is expressed FSH (reviewed in Lin and Achermann, 2008). in prostate cancer cells but not in normal prostate. NR5A1 mutations have also been detected in 46, XY SF-1 expression stimulates local and autonomous patients with severe hypospadia and small inguinal steroid production necessary to induce proliferation testes due to partial dysgenesis and /or a reduced and survival that contribute to aggressive prostate androgen synthesis (Lin et al., 2007). SF-1 was also cancer (Lewis et al., 2014). considered as a candidate gene for bilateral SF-1 overexpression and adrenal anorchidia based on the study of a cohort of 24 boys tumorigenesis where one boy carried a heterozygous NR5A1 Important insights into the key role of SF-1 dosage mutation. He presented one absent testis, one very came from pediatric adrenocortical tumors analysis. small testis with undectable AMH in early infancy, Using comparative genomic hybridization (CGH) and later a testis atrophy in childhood (Philibert et and SNP array profiling, a high frequency of al., 2007). However the patient's twin brother who chromosomal aberrations and amplification of 9q33- harbored the same mutation underwent normal q34 region, harboring the SF-1 gene, emerged as the puberty suggesting that, despite incomplete most consistent finding in a majority childhood penetrance of NR5A1 mutations, SF-1 could adrenocortical tumors (Figueiredo et al., 1999; participate in maintaining the testis. Figueiredo et al., 2005; Pianovski et al., 2006; A study identified heterozygous NR5A1 mutations, Letouzé et al., 2012). SF-1 overexpression has been localized in the hinge region and proximal LBD of shown to increase proliferation of human the protein, associated with spermatogenic failure adrenocortical cells, and to induce adrenocortical (from moderate oligospermia to azoospermia) in tumors in Sf-1 transgenic mice (Doghman et al., healthy men, widening the range of gonadal 2007) (see above). Further studies have shown that phenotypes associated with NR5A1 mutations the levels of SF-1 expression represent a stage- (Bashamboo et al., 2010). independent prognostic indicator in patients with Adrenal insufficiency adrenocortical cancer (Sbiera et al., 2010). SF-1 dosage is then considered as a critical factor in Given the central role of SF-1 in adrenal adrenocortical tumorigenesis (reviewed in Lalli, development and steroidogenesis, several studies 2010). have looked for NR5A1 mutations in children and adults with primary adrenal insufficiency. Only few SF-1 expression in endometriosis cases have been described of NR5A1 mutations that SF-1 is expressed in endometriotic cells whereas it is also produce adrenal insufficiency in addition to not usually detected in normal endometrium and can gonadal defects (Achermann et al., 1999; exert a role in the pathogenesis of endometriosis Achermann et al., 2002; Malikova et al., 2014). A (Xue et al., 2007; reviewed in Bulun et al., 2009). single case of a prepubertal girl where adrenal SF-1 expression leads to an aberrant activation of insufficiency was associated with apparent normal StAR and CYP19 genes expression and to an ovarian development has been reported (Biason- increase of the endogenous synthesis of estrogen Lauber and Schoenle, 2000). within endometriotic tissue, a key causative factor in In another study, no NR5A1 mutations were the disease. This aberrant expression seems to be identified in a small cohort of girls diagnosed with explained by modifications in the regulation of SF-1 adrenal hypoplasia (Lin et al., 2006). expression by DNA methylation of CpG islands in the promoter, intron 1, and exon 2/intron 3 regions Similarly, no significant NR5A1 changes were (Xue et al., 2014). found in boys affected by adrenal hypoplasia without 46 XY, development of sex disorders DAX1 mutations (Lin et al., 2006). Thus, NR5A1 mutations seem not to be a common cause of primary (DSD) adrenal failure in boys without reproductive Note dysfunction or 46,XY DSD. Heterozygous NR5A1 mutations emerge as a Primary ovarian insufficiency (POI) relatively frequent finding in patient with 46,XY DSD from typical to severe phenotype, but without Note adrenal insufficiency. The patients present a NR5A1 mutations have been identified in familial phenotype of ambiguous or female external genitalia and sporadic forms of 46,XX primary ovarian at birth and small inguinal testes. Müllerian insufficiency (Lourenço et al., 2009). These 46XX structures may be present or absent, and Wolffian patients presented either primary or secondary structures are often seen. There is a significant amenorrhea at variable ages. Primary gonadal failure biochemical evidence of partial gonadal dysgenesis was associated with elevated LH and FSH and low with impaired androgen synthesis, that contributes to estrogen levels. These NR5A1 mutations, detected in
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SGK1 (serum/glucocorticoid regulated kinase 1) Miranda Menniti, Rodolfo Iuliano, Lucia D'Antona, Cristina Talarico, Rosario Amato, Nicola Perrotti Dipartimento di Scienze della Salute, Universita degli Studi Magna Graecia di Catanzaro (MM, RA, NP), Dipartimento di Medicina Sperimentale e Clinica, Universita degli Studi Magna Graecia di Catanzaro (RI), Dipartimento di Medicina Sperimentale e Clinica, Universita degli Studi Magna Graecia di Catanzaro (LD, CT)
Published in Atlas Database: September 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/SGK1ID42281ch6q23.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62261/09-2014-SGK1ID42281ch6q23.pdf DOI: 10.4267/2042/62261 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
(AceView). Abstract The SGK1 gene is conserved in chimpanzee, Rhesus Review on SGK1, with data on DNA/RNA, on the monkey, dog, cow, mouse, rat, chicken, zebrafish, protein encoded and where the gene is implicated. and C. elegans (Gene ID: 6446, NCBI). Identity Protein Other names: SGK Note HGNC (Hugo): SGK1 The serum- and glucocorticoid-inducible kinase 1 Location: 6q23.2 (SGK1) was discovered as a gene regulated transcriptionally by serum- and glucocorticoids in rat DNA/RNA mammary tumor cells (Firestone et al., 2003). Description Description The SGK1 gene is comprised of 14 coding exons SGK1 is a member of the "AGC" subfamily (García (Ensembl). Martínez and Alessi, 2008). SGK1 activation is dependent on phosphorylation. mTOR was found to Transcription be the H-motif kinase that phosphorylates Sgk1 at Sgk1 contains 28 distinct gt-ag introns, it presents 32 S422 and PDK1 at T256 (Hong et al., 2008; Amato different mRNAs transcription products with 28 et al., 2007; Kobayashi and Cohen, 1999; Perrotti et alternatively spliced variants and 4 unspliced forms. al., 2001). Sgk1 is involved in mediating growth 8 probable alternative promoters have been factor-, insulin-, IL-2- and steroid-dependent identified, 10 non overlapping alternative last exons survival signals (Lang et al., 2009a; Mikosz et al., and 8 validated alternative polyadenylation sites 2001).
Chain (1-431) serine/threonine-protein kinase Sgk1; domain (98-355) protein kinase; domain (366-431) AGC-kinase C-terminal (UNIPROT).
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 535 SGK1 (serum/glucocorticoid regulated kinase 1) Menniti M, et al.
Expression activity, with and without insulin stimulus (Menniti et al., 2005). SGK1 transcription is regulated by the Moreover, it was demonstrated that the 60 kDa glucocorticoid receptor (GR), the mineralocorticoid Lysophospholipase (LysoLP) interacts with SGK1, receptor (MR), the progesterone receptor (PR), the and that the expression of LysoLP in Xenopus vitamin D receptor (VDR), the retinoid X receptor oocytes decreases membrane expression of ENaC, (RXR), the farnesoid X receptor (FXR), the sterol inhibiting basal and Sgk1-dependent activation of regulatory element binding protein (SREBP), the channel (Menniti et al., 2010). Sgk1 can peroxisome proliferator-activated receptor γ regulates RANBP1 at the gene transcription level (PPARγ), the cAMP response element binding with functional consequences on microtubule protein (CREB), the p53 tumor suppressor protein, stability and cell sensitivity to taxol (Amato et al., the Sp1 transcription factor, the activating protein 1 2013). (AP1), the activating transcription factor 6 (ATF6), Alternative initiation of transcription at -2981, -850 the heat shock factor (HSF), reticuloendotheliosis upstream of the transcription initiation site (+1) of viral oncogene homolog (c-Rel), nuclear factor κB the reference mRNA of SGK1 was studied. (NFκB), signal transducers and activators of Transcription of three distinct splice variants are all transcription (STAT), TGFβ dependent transcription markedly upregulated in tumor tissues but factors SMAD3 and SMAD4, and fork-head activin differentially up-regulated under differentiation or signal transducer (FAST) (Lang et al., 2009a). hypoxia. Localisation SGK presents a stimulus-dependent regulation for Implicated in the subcellular localization. SGK actively shuttles between the nucleus (in S and G2/M) and the Various cancers cytoplasm (in G1) in synchrony with the cell cycle Increased expression of SGK1 have been observed (Buse et al., 1999). The nuclear localization signal in colon cancer, myeloma, medulloblastoma, (NLS) of SGK (located at an external surface of the prostate cancer, ovarian tumors and non-small cell molecule) binds the importin-alpha nuclear import lung cancer (Lang et al., 2013). receptor regulating the nuclear-cytoplasmic shuttling SGK1-sensitive implication in tumour growth (Firestone et al., 2003). include activation of K(+) channels and Ca(2+) SGK-1 localizes in the mitochondria, under channels, Na(+)/H(+) exchanger, amino acid hyperosmotic stress, that permits access to transporters, glucose transporters, upregulation of physiologically appropriate mitochondrial the nuclear factor NFkappaB and beta-catenin and interacting proteins and substrates, such as IF-1 and downregulation of the transcription factors the F1F0-ATPase, as part of the cellular stressed Foxo3a/FKHRL1 and p53 (Lang et al., 2010). induced program (O'Keeffe et al., 2013). SGK1 phosphorylates MDM2 with consequent p53 A significant fraction of SGK-1 is membrane- ubiquitylation, and influences cell proliferation, associated and ubiquitilated (Brickley et al., 2002). survival, and differentiation (Amato et al., 2009). In cancer cells, SGK1 up-regulates RanBP1, a major Function effector of the GTPase RAN, which in turn SGK1 regulates different ion channels, transporters, influences mitotic microtubule activity and transcription factors and enzyme: ion channels like decreases taxol sensitivity (Amato et al., 2013). ENaC (Faletti et al., 2002), TRPV5, ROMK, Kv1.3, SGK1 expression mediated the phosphorylation of KCNE1/KCNQ1, GluR1, GluR6; carriers like ERK2, then the MEK/ERK complexes formation NHE3, GLUT1, SGLT1, EAAT1, EAAT2, EAAT3, during liver regeneration (Won et al., 2009). EAAT4, EAAT5, Na+-K+-ATPase. SGK1 regulates SGK1 negatively regulates stress-activated signaling the activity of enzymes like glycogen synthase through inhibition of SEK1 function (Kim et al., kinase-3, ubiquitin ligase Nedd4-2, 2007). phosphomannomutase-2 and transcription factors SGK1 interferes with the binding of SEK1 to JNK1 like forkhead transcription factor FKHRL1, beta- and MEKK1 (Lang et al., 2010), down-regulates catenin, nuclear factor kappaB. Moreover, SGK1 vinculin phosphorylation, which in turn may contributes to the regulation of transport, hormone enhance migration via actin cytoskeleton release, neuroexcitability, cell proliferation, and redistribution (Schmidt et al., 2012). apoptosis (Lang et al., 2006). SGK1 influences the activity of channels and Sgk1 can phosphorylate and activate MDM2, transporters, such as Ca2+ release-activated driving p53 to degradation, protecting cells from channels (ICRAC) Orai1/STIM (Eylenstein et al., stress dependent apoptosis (Amato et al., 2009). 2012) and the K+ channel Kv1.3, influencing cell Sgk1 was demonstrated to interact with proliferation and cell death (Schmidt et al., 2012). phosphomannomutase 2 (PMM2), inhibiting its SGK1 is a direct beta-catenin target gene and in colon cancer cells its up-regulation determines a
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 536 SGK1 (serum/glucocorticoid regulated kinase 1) Menniti M, et al.
decrease of apoptosis through the down-regulation androgen pathway signaling in these tumors of Foxo3a activity (Dehner et al., 2008). (Szmulewitz et al., 2012). SGK-1 has significant homology with the serine- Inhibition of SGK1 expression or activity threonine Akt which is considered a relevant player antagonizes androgen-induced growth of the in carcinogenesis, since its activation occurred in the prostate cancer cell line LNCaP, suggesting that majority of human tumors. Interestingly, some SGK1 might be a viable target for the treatment of cancer cell lines that are resistant to Akt inhibition prostate cancer (Sherk et al., 2008). showed significant up-regulation of SGK1 Ovarian cancer expression (Sommer et al., 2013). Sgk was identified like a critical FSH-regulated gene Colorectal carcinoma important for the proliferation and maturation of A recent study confirms the sensitivity of colon granulosa cells in the normal ovary (Richards, 1994). carcinoma to the expression of SGK1. Following Specific and reproducible gene expression changes deficiency of APC (adenoma polyposis coli) or occur in human ovarian tumors over time, following chemical cancerogenesis, SGK1 knockout mice systemic administration of glucocorticoids. develop less intestinal tumours than their wild-type Induction of SGK1 gene expression in epithelial littermates and pharmacological SGK1 inhibition tumor cell lines inhibits chemotherapy-induced counteracts growth of cancer cells (Lang et al., tumor cell apoptosis (Melhem et al., 2009). 2010). SGK1 up-regulates RanBP1, a major effector Sgk expression is lower in epithelial tumours, serous of the GTPase RAN, which in turn influences mitotic and mucinous cystadenocarcinomas, and also in microtubule activity and decreases taxol sensitivity normal pre-menopausal ovaries (Chu et al., 2002). in RKO colon carcinoma cells (Amato et al., 2013). Hypertension Kidney cancer There are different SGK1 gene variants that can In A-498 kidney cancer cells, IL-2 binding to its own influence blood pressure (Rao et al., 2013), including receptor triggers a signal transduction pathway the combination of polymorphisms in intron 6 leading to the inhibition of proliferation and [I6CC] and exon 8 [E8CC/CT] (Lang et al., 2006; apoptosis. Inhibition of proliferation is associated Lang et al., 2009a). with Erk1/2 dephosphorylation, whereas the survival The insulin probably stimulates renal tubular salt signals appear to be mediated by Sgk1 activation reabsorption through the activation of SGK1 with (Amato et al., 2007). consequent renal salt retention and hypertension in Myeloma type II diabetes (Lang et al., 2006; Lang et al., 2009a). SGK1 is a highly cytokine-responsive gene in myeloma cells promoting their malignant growth. Diabetes Fagerli et al. recently have demonstrated a rapid, SGK1 regulates the Na+ coupled glucose transporter strong and sustained induction of SGK1 in primary SGLT1 (Lang et al., 2006), the adipocyte myeloma cells. Inhibition of the Janus kinase/signal differentiation and the adipogenesis (Di Pietro et al., transducer and activator of transcription 2010). The I6CC/E8CC/CT SGK1 gene variant (JAK/STAT) pathway abolished STAT3 determines enhancement in body weight and phosphorylation and SGK1 induction. prevalence of type 2 diabetes (Lang et al., 2009b). Downregulation of SGK1 by shRNAs resulted in Thrombosis decreased proliferation of myeloma cell lines, with induction of cell cycle inhibitory genes, like SGK1 stimulates coagulation, through tissue factor CDKNA1/p21, and downregulation of CDK6 and expression (Lang et al., 2009a) and regulation of RBL2/p130 (Fagerli et al., 2011). blood platelets by up-regulation of NFκB, and consequent expression of the platelet Ca2+ channel Prostate cancer Orai1/STIM1, that predisposing to stroke (Dahlberg Rauhala et al. showed the downregulation of mRNA et al., 2011) and thrombosis (Borst et al., 2012). and protein expressions of SGK, in prostate cancer. Autoimmune disease The expression of SGK was decreased in about half of the prostate carcinomas, whereas the expression SGK1 is involved in autoimmune disease, through was high in all non-malignant prostate epithelial up-regulation of the pathogenic IL-23-dependent cells (Rauhala et al., 2005). interleukin (IL) 17-producing CD4+ helper T cells Low espression of SGK1 is associated with higher (TH17 cells) (Kleinewietfeld et al., 2013). tumor grade and increased cancer recurrence, and is In affected tissues of inflammatory and fibrosing a potential indicator of aberrant androgen receptor diseases was demonstrated an excessive expression signaling. Glucocorticoid receptor expression of SGK1, like in lung fibrosis, diabetic nephropathy, increased with androgen deprivation, potentially glomerulonephritis, experimental nephrotic providing a mechanism for the maintenance of syndrome, obstructive nephropathy, liver scirrhosis,
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fibrosing pancreatitis, peritoneal fibrosis, Crohn’s You H, Jang Y, You-Ten AI, Okada H, Liepa J, Wakeham disease, and coeliac disease (Cheng et al., 2010; A, Zaugg K, Mak TW. p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Lang et al., 2006; Yamahara et al., 2009). Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14057-62 Feng Y, Wang Q, Wang Y, Yard B, Lang F. SGK1-mediated References fibronectin formation in diabetic nephropathy. Cell Physiol Richards JS. Hormonal control of gene expression in the Biochem. 2005;16(4-6):237-44 ovary. Endocr Rev. 1994 Dec;15(6):725-51 Menniti M, Iuliano R, Amato R, Boito R, Corea M, Le Pera I, Buse P, Tran SH, Luther E, Phu PT, Aponte GW, Firestone Gulletta E, Fuiano G, Perrotti N. Serum and glucocorticoid- GL. 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Leukaemia Section Short Communication t(14;17)(q32;q21) IGH/IGF2BP1 Guangyu Gu, Sarah South Genetics Associates, Inc. Nashville, TN [email protected] (GG); Department of Pathology, University of Utah; ARUP Institute for Clinical, Experimental Pathology, ARUP Laboratories, Salt Lake City, UT [email protected] (SS)
Published in Atlas Database: October 2014 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1417q32q21IGH-IGF2BP1ID1706.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62262/10-2014-t1417q32q21IGH-IGF2BP1ID1706.pdf DOI: 10.4267/2042/62262 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Genes involved and IGH rearrangements are a common chromosomal proteins abnormality seen in lymphoproliferative disorders, IGH including ALL. Numerous translocation partners of IGH gene have been identified. Here we report a B- Location ALL case with a t(14;17)(q32;q21) IGH/IGF2BP1. 14q32 Keywords IGF2BP1 IGH partner, t(14;17)(q32;q21), IGF2BP1, acute B Protein lymphoblastic leukemia IGF2BP1 is a member of Insulin-like growth factor 2 mRNA-binding protein family; pro-oncogenic Clinics and pathology RNA-binding; post-transcriptional regulation of gene expression (Bell et al., 2013; Lederer et al., Disease 2014). B-cell acute lymphoblastic leukemia (ALL) Phenotype/cell stem origin CD10+, CD19+, CD38+, cytoplastic CD22+ ALL Epidemiology Only one case, a 16 year old boy (Gu et al., 2014) Clinics Severe pancytopenia and an elevated lactate t(14;17)(q32;q21) G- Banding dehydrogenase (1048U/L); WBC was 2.7 X 10 9 with 20% blasts; no central nervous system Result of the chromosomal involvement. anomaly Cytogenetics Hybrid gene Description Cytogenetics morphological likely head-to-head fusion of IGF2BP1 with the IGH An additional copy of the derivative 14 was found locus.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 541 t(14;17)(q32;q21) IGH/IGF2BP1 Gu G, South S
Fusion protein Gu G, Sederberg MC, Drachenberg MR, South ST. IGF2BP1: a novel IGH translocation partner in B acute Oncogenesis lymphoblastic leukemia. Cancer Genet. 2014 Jul- Overexpression of the IGF2BP1 gene. Aug;207(7-8):332-4 Lederer M, Bley N, Schleifer C, Hüttelmaier S. The role of References the oncofetal IGF2 mRNA-binding protein 3 (IGF2BP3) in cancer. Semin Cancer Biol. 2014 Dec;29:3-12 Bell JL, Wächter K, Mühleck B, Pazaitis N, Köhn M, Lederer M, Hüttelmaier S. Insulin-like growth factor 2 mRNA-binding This article should be referenced as such: proteins (IGF2BPs): post-transcriptional drivers of cancer progression? Cell Mol Life Sci. 2013 Aug;70(15):2657-75 Gu G and South S. t(14;17)(q32;q21) IGH/IGF2BP1. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8):541-542.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 542 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Leukaemia Section Short Communication t(5;12)(q33;p13) ATF7IP/PDGFRB Kenichiro Kobayashi Department of Pediatric Hematology and Oncology Research Institute, National Center for Child Health and Development, 2-10-1 Okura Setagaya-ku Tokyo,157-8535, Japan. [email protected]
Published in Atlas Database: October 2014 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0512q33p13ID1708.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62263/10-2014-t0512q33p13ID1708.pdf DOI: 10.4267/2042/62263 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
he has maintained complete molecular remission for Abstract 12 months (Kobayashi K.et al, 2014). Ph-like ALL is characterized by several Prognosis chromosomal translocations involving activating cytokine receptor or tyrosine kinase such as CRLF2, As was shown in Ph-like ALL bearing PDGFRB ABL1, JAK2, and PDGFRB (Robert K.G et al, translocation, i.e. EBF1/PDGFRB, t(5;12)(q33;p13) 2014). Recent increasing evidences suggest that ATF7IP/PDGFRB translocation seems response to patients with Ph-like ALL bearing PDGFRB TKI. translocation are potentiated to respond to tyrosine kinase inhibitors. Thus, this translocation should be Cytogenetics included within the molecular companion Cytogenetics morphological diagnostics to facilitate tailor-made cancer therapy. Banding cytogenetics revealed 45, XY, -7, add (12) Keywords (p13). The mRNA sequence analysis identified an Ph-like acute lymphoblastic leukemia, tyrosine in-frame transcript fusing exon 13 of ATF7IP with kinase inhibitor (TKI), PDGFRB exon 11 of PDGFRB, i.e. t(5;12)(q33;p13). Clinics and pathology Genes involved and Disease proteins Ph-like acute lymphoblastic leukemia PDGFRB Clinics Location The patient is an 8-year-old male with B-ALL. Initial 5q33 cytogenetics analysis showed a 45, XY, -7, add (12) (p13). RNA sequence analysis identified a novel Protein translocation of ATF7IP/PDGFRB (Kobayashi K.et PDGFRB is a frequent target of chromosomal al, 2013). He showed good response to standard risk translocation in a broad spectrum of hematological ALL therapy, but he relapsed even in the malignancies. continuation of the maintenance chemotherapy at 26 ATF7IP months after the diagnosis. He received 3 course of Location salvage therapies following by stem cell 12p13 transplantation. Second generation dasatinib was commenced with the minimum residual disease Protein (MRD) at day 60 post-transplant. The therapeutic ATF7IP acts as transcriptional regulators and is response was prompt, with the disappearance of frequently overexpressed in cancer cells modulating genomic-PCR based on MRD within 3 months, and
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 543 t(5;12)(q33;p13) ATF7IP/PDGFRB Kobayashi K
telomerase TERT and TERC gene expression (Liu, coiled-coil domain from 5' ATF7IP- would favour L. et al, 2009). subsequent constitutive activation of the PDGFRB tyrosine kinase domain. Result of the chromosomal anomaly References Kobayashi K, Miyagawa N, Mitsui K, Matsuoka M, Kojima Hybrid gene Y, Takahashi H, Ootsubo K, Nagai J, Ueno H, Ishibashi T, Sultana S, Okada Y, Akimoto S, Okita H, Matsumoto K, Description Goto H, Kiyokawa N, Ohara A. TKI dasatinib monotherapy 5' ATF7IP-3' PDGFRB for a patient with Ph-like ALL bearing ATF7IP/PDGFRB translocation. Pediatr Blood Cancer. 2015 Jun;62(6):1058- Fusion protein 60
Description This article should be referenced as such: Forced expression of ATF7IP/PDGFRB, not wild- type PDGFRB, conferred growth factor Kobayashi K. t(5;12)(q33;p13) ATF7IP/PDGFRB. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8):543-544. independence to murine Ba/F3cells, indicating that
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 544 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Solid Tumour Section Review
Lung: Translocations in Squamous Cell Carcinoma Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: October 2014 Online updated version : http://AtlasGeneticsOncology.org/Tumors/TranslocLungSquamCellCarcID6819.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62264/10-2014-TranslocLungSquamCellCarcID6819.pdf DOI: 10.4267/2042/62264 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
(sarcomatoid) carcinosarcoma variants of the typical Abstract squamous cell carcinoma. The expression of cytokeratins (CK) CK5/6, Review on translocations in lung squamous cell CK34BE12 and TP63 (3q28, also called P63) are carcinoma, with data on clinics, genetics and strong in squamous cell carcinoma, whereas the cytogenetics. expression of CK7 and NKX2-1 (14q13, also called TTF-1) are strong in adenocarcinoma (Xu et al., Classification 2014). In the group of malignant epithelial tumours of the Evolution lungs, squamous cell carcinomas belong to the non- Staging is performed according to the TNM system. small cell carcinomas (non-small cell lung cancer (NSCLC)), as opposed to small cell carcinomas Genetics (SCLC). Other NSCLCs are: adenocarcinomas, adenosquamous carcinomas, large cell carcinomas, Note sarcomatoid carcinomas, carcinoid tumours, salivary TP53 (17p13) mutations are detected in most cases. gland tumours. In a large recent study, altered pathways included NFE2L2/KEAP1 in 34%, squamous differentiation Clinics and pathology genes in 44%, PI3K/AKT in 47%, and CDKN2A/RB1 in 72% of tumors. In contrast to what Epidemiology is found in adenocarcinoma, mutations in EGFR Squamous cell carcinoma is the most frequent lung (7p11) or in KRAS (12p12) are extremely rare in cancer in male patients, representing about 40% of squamous cell carcinoma of the lungs (Cancer the cases, and only 25% in women (much less Genome Atlas Research Network, 2012). DDR2 frequent in female patients than adenocarcinoma). (1q23) is inactivated in about 4% of cases; FGFR1 Squamous cell carcinoma is the lung cancer the most (8p11) and FGFR3 (4p16) are amplified in 5 to 10% often associated with tobacco smoking. Location of of cases (Majewski et al., 2013; Seo et al., 2014). the tumour is usually central, present as a perihilar mass, with or without lobar collapse and obstructive Cytogenetics pneumonitis, but it can also be peripheral at times. Note Pathology Of 157 translocations so far reported in squamous There are small cell variants (differential diagnosis: cell carcinoma of the lungs, 1 gene was found five SCLC), clear cell variants, well-differentiated times implicated: ATP11B (3q26, which catalyzes papillary variants, basaloid variants with a very the hydrolysis of ATP); 1 gene was implicated in aggressive clinical course, and spindle cell three different translocations: MCF2L2 (3q27, a
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guanine nucleotide exchange factor); and 13 genes t(2;2)(p25;p25) ROCK2/SH3YL1 (Cancer Genome were found twice: ANGPT1 (8q23), EIF4EBP1 Atlas Research Network, 2012) (8p11), EML4 (2p21), IGF2 (11p15), ITSN1 t(2;2)(p24;p23) GPN1/KLHL29 (Cancer Genome (21q22), KLHL29 (2p24), MAN1A2 (1p13), Atlas Research Network, 2012) MGAT5 (2q21), NPAS3 (14q13), PPP6R3 (14q13), inv(2)(p21p23) or del(2)(p21p23) EML4/ALK ROS1 (6q22), TMCC1 ( 3q22), and TTC28 (22q12). (Rikova et al., 2007; Soda et al., 2007; Martelli et al., Finally, 280 genes were found implicated in one 2009) translocation. t(2;2)(p21;p21) THADA/EML4 (Cancer Genome Cytogenetics Morphological Atlas Research Network, 2012) t(2;2)(p16;p23) PSME4/PPP1CB (Cancer Genome The translocations are the following: Atlas Research Network, 2012) t(1;1)(p36;p36) PRKCZ/SKI (Majewski et al., 2013) t(2;2)(p15;p15) EHBP1/FAM161A (Cancer t(1;1)(p34;q44) SMYD3/ELOVL1 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(2;2)(q21;q21) GPR39/MGAT5 (Cancer Genome t(1;1)(q21;q21) GATAD2B/PRKAB2 (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(2;2)(q21;q24) ACVR1C/MGAT5 (Cancer t(1;2)(p35;q37) ZBTB8B/TRAF3IP1 (Cancer Genome Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(2;2)(q23;q35) TNS1/RPRM (Cancer Genome t(1;2)(p12;p16) REL/MAN1A2 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(2;3)(p16;q26) KCNMB2/NRXN1 (Cancer t(1;2)(p12;p15) PHGDH/WDPCP (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(2;4)(p16;q13) BCL11A/EPHA5 (Cancer Genome t(1;3)(p34;q26) ATP11B/POU3F1 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(2;5)(p16;p15) NRXN1/PLEKHG4B (Cancer t(1;3)(p34;q26) OSCP1/SOX2-OT (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(2;5)(p11;p12) HCN1/FUNDC2P2 (Cancer t(1;3)(p33;q29) TFRC/NSUN4 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(2;5)(q35;p13) USP37/OSMR (Cancer Genome t(1;4)(p31;q22) BMPR1B/ALG6 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(2;6)(p24;p22) ID4/FAM84A (Cancer Genome t(1;5)(p34;q31) CTNNA1/HEYL (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(2;16)(q24;q11) ANKRD26P1/SLC4A10 (Cancer t(1;5)(q25;p13) DARS2/ZFR (Cancer Genome Atlas Genome Atlas Research Network, 2012) Research Network, 2012) t(2;17)(p25;q21) CRHR1-IT1/ALLC (Cancer t(1;8)(p36;q21) SLC7A13/WDTC1 (Cancer Genome Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(2;18)(p24;q11) KLHL29/PSMA8 (Cancer t(1;8)(p32;q24) NRD1/KCNK9 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(2;22)(p12;q12) EVA1A/TTC28 (Cancer Genome t(1;9)(p33;p13) KIF24/FAAH (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(3;3)(p12;q29) PAK2/VGLL3 (Cancer Genome t(1;10)(p32;q21) CDK1/USP24 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(3;3)(q11;q13) ALCAM/EPHA6 (Cancer Genome t(1;10)(p31;p14) SFMBT2/PRKACB (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(3;3)(q12;q13) GSK3B/IMPG2 (Cancer Genome t(1;10)(q32;q22) TMEM206/PSAP (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(3;3)(q13;q22) SLCO2A1/GUCA1C (Cancer t(1;11)(p31;q24) ETS1/NEGR1 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(3;3)(q21;q22) RUVBL1/TMCC1 (Cancer Genome t(1;12)(q25;p12) HMCN1/ETNK1 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(3;3)(q22;q22) PIK3CB/BFSP2 (Cancer Genome t(1;16)(q21;p12) CCP110/GOLPH3L (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(3;3)(q22;q22) TMCC1/C3orf36 (Cancer Genome t(1;17)(p21;q25) UNK/DPYD (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(3;3)(q24;q26) HLTF/OTOL1 (Cancer Genome t(1;17)(p12;q11) ALDOC/MAN1A2 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(1;21)(p35;q22) ITSN1/MATN1 (Cancer Genome t(3;3)(q25;q25) GMPS/C3orf55 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012)
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t(3;3)(q25;q26) IQCJ/BCHE (Cancer Genome Atlas t(5;5)(p12;p13) RICTOR/FGF10 (Cancer Genome Research Network, 2012) Atlas Research Network, 2012) t(3;3)(q25;q27) PPM1L/MCF2L2 (Cancer Genome t(5;6)(q33;q22) CD74/ROS1 (Davies et al., 2012) Atlas Research Network, 2012) t(5;8)(p15;q21) MRPS28/ADAMTS16 (Cancer t(3;3)(q25;q28) PYDC2/C3orf79 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(5;8)(p13;p11) EIF4EBP1/PRKAA1 (Cancer t(3;3)(q26;q26) ATP11B/SI (Cancer Genome Atlas Genome Atlas Research Network, 2012) Research Network, 2012) t(5;11)(q14;q22) FAM151B/CASP12 (Cancer t(3;3)(q26;q26) PHC3/FNDC3B (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(5;11)(q35;q14) KCNIP1/KCTD14 (Cancer t(3;3)(q26;q27) CCDC39/MCF2L2 (Cancer Genome Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(5;12)(p12;q13) NNT/AMIGO2 (Cancer Genome t(3;3)(q26;q28) SOX2/TPRG1 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(6;6)(p25;p25) FAM50B/PPP1R3G (Cancer t(3;3)(q27;q28) LPP/ST6GAL1 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(6;6)(p22;q12) EYS/DEK (Cancer Genome Atlas t(3;3)(q27;q29) EHHADH/SENP5 (Cancer Genome Research Network, 2012) Atlas Research Network, 2012) t(6;6)(p21;p21) HLA-DOA/MUC21 (Cancer t(3;3)(q29;q29) LRCH3/MIR570 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(6;6)(p12;p22) BEND6/TRIM38 (Cancer Genome t(3;4)(q26;p16) ATP11B/ZNF595 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(6;6)(p12;q14) FAM83B/HTR1E (Cancer Genome t(3;8)(q27;q22) MCF2L2/MIR548A3 (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(6;6)(q14;q15) GABRR2/ME1 (Cancer Genome t(3;8)(q29;p12) FYTTD1/WRN (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(6;13)(p21;q12) RPL7L1/CDK8 (Cancer Genome t(3;11)(q26;p15) PDE3B/ATP11B (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(6;14)(q24;q24) SASH1/DPF3 (Cancer Genome t(3;13)(q21;q33) TNFSF13B/MYLK (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(6;16)(q13;p13) NTAN1/SLC17A5 (Cancer t(3;17)(q25;p11) MAP2K3/SSR3 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(7;7)(p11;p12) VOPP1/GRB10 (Cancer Genome t(3;17)(q29;q23) MIR21/WDR53 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(7;7)(q22;q31) ANKRD7/DUS4L (Cancer Genome t(3;19)(q27;q13) ACTN4/IGF2BP2 (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(7;7)(q31;q33) CHCHD3/MET (Cancer Genome t(3;20)(q21;q13) SLC12A8/BCAS1 (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(7;8)(p14;p23) AMPH/FDFT1 (Majewski et al., t(3;21)(p11;q21) POU1F1/TMPRSS15 (Cancer 2013) Genome Atlas Research Network, 2012) t(7;10)(q36;q25) ACTR3C/SORCS1 (Cancer t(3;22)(q26;q11) ATP11B/TPTEP1 (Cancer Genome Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(8;8)(p11;p11) ADAM9/RNF170 (Cancer Genome del(4)(p16p16) FGFR3/TACC3 (Majewski et al., Atlas Research Network, 2012) 2013; Wu et al. 2013) t(8;8)(p11;p11) BAG4/FGFR1 (Wu et al., 2013) t(4;4)(q13;q22) CCSER1/UGT2A1 (Cancer t(8;8)(p11;p11) LETM2/KCNU1 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(4;6)(p15;q22) SLC34A2/ROS1 (Davies et al., t(8;8)(q11;q11) PRKDC/C8orf22 (Cancer Genome 2012) Atlas Research Network, 2012) t(4;8)(q13;q24) COX18/ZFAT (Cancer Genome t(8;8)(q23;q23) CSMD3/ANGPT1 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(4;9)(q13;q32) ADAMTS3/SNX30 (Cancer t(8;8)(q23;q23) OXR1/RSPO2 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(4;10)(p13;q11) SGMS1/KCTD8 (Cancer Genome t(8;9)(p12;p13) PURG/UBAP1 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(5;5)(p15;p15) MARCH6/IRX4 (Cancer Genome t(8;9)(p11;p21) EIF4EBP1/C9orf53 (Cancer
Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(5;5)(p15;p15) ROPN1L/SEMA5A (Cancer t(8;10)(p21;q26) FGFR2/KIAA1967 (Wu et al., Genome Atlas Research Network, 2012) 2013)
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t(8;10)(q23;q11) ANGPT1/CXCL12 (Cancer t(16;22)(p12;q11) POM121L4P/LCMT1 (Cancer Genome Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(8;11)(q21;p15) HTATIP2/CA1 (Cancer Genome t(17;17)(p13;p11) PIGL/RABEP1 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(8;15)(q21;q21) NEDD4/RDH10 (Cancer Genome t(17;17)(p11;q11) AKAP10/PSMD11 (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(8;16)(p11;p12) KIAA0556/LSM1 (Cancer t(17;17)(p11;q11) KIAA0100/ALKBH5 (Cancer Genome Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(8;16)(q22;q24) GSE1/NACAP1 (Cancer Genome t(17;17)(q23;q23) RPS6KB1/VMP1 (Majewski et Atlas Research Network, 2012) al., 2013) t(8;21)(q11;q21) UBE2V2/NRIP1 (Cancer Genome t(18;22)(q12;q11) CDC45/RIT2 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(9;9)(p21;p21) CDKN2A/FOCAD (Cancer t(19;19)(p13;p12) UNC13A/ZNF492 (Cancer Genome Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(9;9)(p21;p13) PLAA/RUSC2 (Cancer Genome t(19;19)(q13;q13) BCL3/HIPK4 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(9;19)(p13;p13) FAM219A/S1PR5 (Cancer t(19;19)(q13;q13) SIPA1L3/CD22 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) inv(10)(p11q11) KIF5B/RET (Cai et al., 2013) t(19;21)(p13;q22) ITSN1/ZNF490 (Cancer Genome t(10;11)(q21;p15) CTNNA3/IGF2 (Cancer Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(19;22)(p12;q11) MMP11/ZNF714 (Cancer t(10;11)(q22;q14) P4HA1/TRIM77P (Cancer Genome Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(20;20)(q11;q13) ADNP/DLGAP4 (Cancer t(10;17)(q22;q12) SAMD8/LHX1 (Cancer Genome Genome Atlas Research Network, 2012) Atlas Research Network, 2012) t(20;22)(q11;q12) PISD/RBL1 (Cancer Genome t(10;20)(q23;q13) WAPAL/PTPRT (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(22;22)(q11;q11) THAP7/PRODH (Cancer t(11;11)(p14;p13) EIF3M/MPPED2 (Cancer Genome Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(22;22)(q12;q12) APOL3/ISX (Cancer Genome t(11;11)(p11;q12) OR9Q1/OR4C46 (Cancer Atlas Research Network, 2012) Genome Atlas Research Network, 2012) t(22;22)(q12;q12) MCM5/TOM1 (Majewski et al., t(11;11)(q12;q12) P2RX3/RTN4RL2 (Majewski et 2013) al., 2013) t(11;11)(q12;q13) EEF1G/PPP6R3 (Cancer Genome References Atlas Research Network, 2012) Cai W, Su C, Li X, Fan L, Zheng L, Fei K, Zhou C. KIF5B- t(11;11)(q12;q13) SHANK2/MS4A8B (Cancer RET fusions in Chinese patients with non-small cell lung Genome Atlas Research Network, 2012) cancer. Cancer. 2013 Apr 15;119(8):1486-94 t(11;11)(q13;q22) PPP6R3/CNTN5 (Cancer Cancer Genome Atlas Research Network. Comprehensive Genome Atlas Research Network, 2012) genomic characterization of squamous cell lung cancers. t(11;12)(p11;p13) ERC1/SPI1 (Cancer Genome Nature. 2012 Sep 27;489(7417):519-25 Atlas Research Network, 2012) Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, t(12;20)(q12;q13) TAF4/ALG10B (Cancer Genome Berge EM, Terracciano LM, Cappuzzo F, Incarbone M, Atlas Research Network, 2012) Roncalli M, Alloisio M, Santoro A, Camidge DR, Varella- Garcia M, Doebele RC. Identifying and targeting ROS1 t(12;22)(q14;q12) SLC16A7/TTC28 (Cancer gene fusions in non-small cell lung cancer. Clin Cancer Res. Genome Atlas Research Network, 2012) 2012 Sep 1;18(17):4570-9 t(13;20)(q12;p12) MACROD2/MPHOSPH8 Majewski IJ, Mittempergher L, Davidson NM, Bosma A, (Cancer Genome Atlas Research Network, 2012) Willems SM, Horlings HM, de Rink I, Greger L, Hooijer GK, t(14;14)(q11;q13) NPAS3/OXA1L (Cancer Genome Peters D, Nederlof PM, Hofland I, de Jong J, Wesseling J, Atlas Research Network, 2012) Kluin RJ, Brugman W, Kerkhoven R, Nieboer F, Roepman t(14;14)(q12;q13) FOXG1/NPAS3 (Cancer Genome P, Broeks A, Muley TR, Jassem J, Niklinski J, van Zandwijk N, Brazma A, Oshlack A, van den Heuvel M, Bernards R. Atlas Research Network, 2012) Identification of recurrent FGFR3 fusion genes in lung t(14;14)(q13;q21) MBIP/C14orf183 (Cancer cancer through kinome-centred RNA sequencing. J Pathol. Genome Atlas Research Network, 2012) 2013 Jul;230(3):270-6 t(14;14)(q13;q21) SEC23A/IGBP1P1 (Cancer Martelli MP, Sozzi G, Hernandez L, Pettirossi V, Navarro Genome Atlas Research Network, 2012) A, Conte D, Gasparini P, Perrone F, Modena P, Pastorino t(16;16)(q12;q13) FTO/HERPUD1 (Majewski et al., U, Carbone A, Fabbri A, Sidoni A, Nakamura S, 2013) Gambacorta M, Fernández PL, Ramirez J, Chan JK, t(16;16)(q23;q24) JPH3/OSGIN1 (Cancer Genome Grigioni WF, Campo E, Pileri SA, Falini B. EML4-ALK Atlas Research Network, 2012)
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 548
Lung: Translocations in Squamous Cell Carcinoma Huret JL
rearrangement in non-small cell lung cancer and non-tumor Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, lung tissues. Am J Pathol. 2009 Feb;174(2):661-70 Cao X, Lonigro RJ, Vats P, Wang R, Lin SF, Cheng AJ, Kunju LP, Siddiqui J, Tomlins SA, Wyngaard P, Sadis S, Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Roychowdhury S, Hussain MH, Feng FY, Zalupski MM, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Talpaz M, Pienta KJ, Rhodes DR, Robinson DR, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan Chinnaiyan AM. Identification of targetable FGFR gene J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, fusions in diverse cancers. Cancer Discov. 2013 Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb Jun;3(6):636-47 MJ. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007 Dec Xu XY, Yang GY, Yang JH, Li J. Analysis of clinical 14;131(6):1190-203 characteristics and differential diagnosis of the lung biopsy specimens in 99 adenocarcinoma cases and 111 squamous Seo AN, Jin Y, Lee HJ, Sun PL, Kim H, Jheon S, Kim K, Lee cell carcinoma cases: utility of an immunohistochemical CT, Chung JH. FGFR1 amplification is associated with poor panel containing CK5/6, CK34βE12, p63, CK7 and TTF-1. prognosis and smoking in non-small-cell lung cancer. Pathol Res Pract. 2014 Oct;210(10):680-5 Virchows Arch. 2014 Nov;465(5):547-58 Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, This article should be referenced as such: Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Huret JL. Lung: Translocations in Squamous Cell Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Carcinoma. Atlas Genet Cytogenet Oncol Haematol. Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the 2015; 19(8):545-549. transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007 Aug 2;448(7153):561-6
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(8) 549 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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