Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice
- PMID: 21403399
- PMCID: PMC3070608
- DOI: 10.1172/JCI45784
Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice
Abstract
Biochemical studies have suggested conflicting roles for the E3 ubiquitin ligase constitutive photomorphogenesis protein 1 (Cop1; also known as Rfwd2) in tumorigenesis, providing evidence for both the oncoprotein c-Jun and the tumor suppressor p53 as its targets. Here we present what we believe to be the first in vivo investigation of the role of Cop1 in cancer etiology. Using an innovative genetic approach to generate an allelic series of Cop1, we found that Cop1 hypomorphic mice spontaneously developed malignancy at a high frequency in the first year of life and were highly susceptible to radiation-induced lymphomagenesis. Further analysis revealed that c-Jun was a key physiological target for Cop1 and that Cop1 constitutively kept c-Jun at low levels in vivo and thereby modulated c-Jun/AP-1 transcriptional activity. Importantly, Cop1 deficiency stimulated cell proliferation in a c-Jun-dependent manner. Focal deletions of COP1 were observed at significant frequency across several cancer types, and COP1 loss was determined to be one of the mechanisms leading to c-Jun upregulation in human cancer. We therefore conclude that Cop1 is a tumor suppressor that functions, at least in part, by antagonizing c-Jun oncogenic activity. In the absence of evidence for a genetic interaction between Cop1 and p53, our data strongly argue against the use of Cop1-inhibitory drugs for cancer therapy.
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Comment in
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Good COP1 or bad COP1? In vivo veritas.J Clin Invest. 2011 Apr;121(4):1263-5. doi: 10.1172/JCI57080. Epub 2011 Mar 14. J Clin Invest. 2011. PMID: 21403396 Free PMC article.
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Tumour suppression: Shedding light on degradation.Nat Rev Cancer. 2011 Jun 9;11(7):466. doi: 10.1038/nrc3089. Nat Rev Cancer. 2011. PMID: 21654816 No abstract available.
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