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Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice

(2011) JOURNAL OF CLINICAL INVESTIGATION. 121(4). p.1329-1343
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Abstract
Biochemical studies have suggested conflicting roles for the E3 ubiquitin ligase constitutive photomorphogenesis protein 1 (Cop 1; 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.
Keywords
CELL-CYCLE PROGRESSION, N-TERMINAL KINASE, UBIQUITIN LIGASE COP1, IN-VIVO, TRANSCRIPTIONAL ACTIVITY, PROSTATE-CANCER, TRANSGENIC MICE, BETHESDA PROPOSALS, NEGATIVE REGULATOR, MOUSE DEVELOPMENT

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Chicago
Migliorini, Domenico, Sven Bogaerts, Dieter Defever, Rajesh Vyas, Geertrui Denecker, Enrico Radaelli, Aleksandra Zwolinska, et al. 2011. “Cop1 Constitutively Regulates c-Jun Protein Stability and Functions as a Tumor Suppressor in Mice.” Journal of Clinical Investigation 121 (4): 1329–1343.
APA
Migliorini, D., Bogaerts, S., Defever, D., Vyas, R., Denecker, G., Radaelli, E., Zwolinska, A., et al. (2011). Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice. JOURNAL OF CLINICAL INVESTIGATION, 121(4), 1329–1343.
Vancouver
1.
Migliorini D, Bogaerts S, Defever D, Vyas R, Denecker G, Radaelli E, et al. Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice. JOURNAL OF CLINICAL INVESTIGATION. 2011;121(4):1329–43.
MLA
Migliorini, Domenico, Sven Bogaerts, Dieter Defever, et al. “Cop1 Constitutively Regulates c-Jun Protein Stability and Functions as a Tumor Suppressor in Mice.” JOURNAL OF CLINICAL INVESTIGATION 121.4 (2011): 1329–1343. Print.
@article{1968069,
  abstract     = {Biochemical studies have suggested conflicting roles for the E3 ubiquitin ligase constitutive photomorphogenesis protein 1 (Cop 1; 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.},
  author       = {Migliorini, Domenico and Bogaerts, Sven and Defever, Dieter and Vyas, Rajesh and Denecker, Geertrui and Radaelli, Enrico and Zwolinska, Aleksandra and Depaepe, Vanessa and Hochepied, Tino and Skarnes, William C and Marine, Jean-Christophe},
  issn         = {0021-9738},
  journal      = {JOURNAL OF CLINICAL INVESTIGATION},
  language     = {eng},
  number       = {4},
  pages        = {1329--1343},
  title        = {Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice},
  url          = {http://dx.doi.org/10.1172/JCI45784},
  volume       = {121},
  year         = {2011},
}

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