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.
Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice / D. Migliorini, S. Bogaerts, D. Defever, R. Vyas, G. Denecker, E. Radaelli, A. Zwolinska, V. Depaepe, T. Hochepied, W. C. Skarnes, J. Marine. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 121:4(2011 Apr), pp. 1329-1343.
|Titolo:||Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice|
|Parole Chiave:||Ubiquitin-protein ligases ; animals ; tumor suppressor protein p53 ; transcription factor AP-1; protein stability ; humans ; mice ; RNA, small interfering ; mice, transgenic ; cell proliferation ; tumor suppressor proteins ; pregnancy ; mice, 129 strain ; neoplasms ; Base Sequence ; MAP kinase signaling system ; mice, mutant strains ; nuclear proteins ; heterozygote ; JNK mitogen-activated protein kinases ; mice, inbred C57BL ; female ; male|
|Settore Scientifico Disciplinare:||Settore VET/03 - Patologia Generale e Anatomia Patologica Veterinaria|
|Data di pubblicazione:||apr-2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1172/JCI45784|
|Appare nelle tipologie:||01 - Articolo su periodico|