COP1 is a tumour suppressor that causes degradation of ETS transcription factors

Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Nature (Impact Factor: 41.46). 06/2011; 474(7351):403-6. DOI: 10.1038/nature10005
Source: PubMed


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.

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Available from: Vishva Dixit
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    • "DISCUSSION Mammalian COP1 is a known tumor suppressor whose downregulation promotes prostatic epithelial cell proliferation and tumorigenesis. Specifically, it regulates p53 protein level by acting as an E3 ubiquitin ligase of p53 (Dornan et al., 2004; Migliorini et al., 2011; Vitari et al., 2011). Human NOSIP/RUL, a homolog of Arabidopsis CSU1, also acts as an E3 ubiquitin ligase and mediates the ubiquitination of EpoR. "
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    • "However, it is worth noting that the truncated ETV1 encoded by TMPRSS2:ETV1 loses the major RFWD2 binding ability and becomes more stable than its wild-type counterpart. Animal model studies further verified that RFWD2 deficiency upregulated ETV1 level and enhanced uncontrolled cellular growth and early stage of prostate malignancy [51]. "
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    • "Surprisingly, despite an ETV1 gene rearrangement [14], and high ETV1 mRNA levels [25], ETV1 protein was not observed in LNCaP cells. However, this is consistent with results from Vitari et al. who showed low ETV1 protein levels in LNCaP cells due to proteasomal targeting by the COP1 E3 ubiquitin ligase [26]. "
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