title: COP1 is a tumour suppressor that causes degradation of ETS transcription factors.
abstract: The proto-oncogenes ETV1, ETV4 and ETV5 encode transcription factors in the E26 transformation-specific (ETS) family, which includes the most frequently rearranged and overexpressed genes in prostate cancer. Despite being critical regulators of development, little is known about their post-translational regulation. Here we identify the ubiquitin ligase COP1 (also known as RFWD2) as a tumour suppressor that negatively regulates ETV1, ETV4 and ETV5. ETV1, which is mutated in prostate cancer more often, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs and was 50-fold more stable than wild-type ETV1. Almost all patient translocations render ETV1 insensitive to COP1, implying that this confers a selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 and produced increased cell proliferation, hyperplasia, and early prostate intraepithelial neoplasia. Combined loss of COP1 and PTEN enhanced the invasiveness of mouse prostate adenocarcinomas. Finally, rare human prostate cancer samples showed hemizygous loss of the COP1 gene, loss of COP1 protein, and elevated ETV1 protein while lacking a translocation event. These findings identify COP1 as a tumour suppressor whose downregulation promotes prostatic epithelial cell proliferation and tumorigenesis.
authors.affiliation: Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Alberto C
authors.initials: AC
authors.lastname: Vitari
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Leong
authors.forename: Kim
authors.initials: K
authors.lastname: Newton
authors.forename: Cindy
authors.initials: C
authors.lastname: Yee
authors.forename: Karen
authors.initials: K
authors.lastname: O'Rourke
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Lilian
authors.initials: L
authors.lastname: Phu
authors.forename: Rajesh
authors.initials: R
authors.lastname: Vij
authors.forename: Ronald
authors.initials: R
authors.lastname: Ferrando
authors.forename: Suzana S
authors.initials: SS
authors.lastname: Couto
authors.forename: Sankar
authors.initials: S
authors.lastname: Mohan
authors.forename: Ajay
authors.initials: A
authors.lastname: Pandita
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Hongo
authors.forename: David
authors.initials: D
authors.lastname: Arnott
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Wertz
authors.forename: Wei-Qiang
authors.initials: WQ
authors.lastname: Gao
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: French
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; C482641:DET1 protein, human; D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D009687:Nuclear Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C471981:COP1 protein, human; C471982:COP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse