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

Domenico Migliorini UGent, Sven Bogaerts UGent, Dieter Defever UGent, Rajesh Vyas, Geertrui Denecker UGent, Enrico Radaelli, Aleksandra Zwolinska UGent, Vanessa Depaepe UGent, Tino Hochepied UGent and William C Skarnes, et al. (2011) JOURNAL OF CLINICAL INVESTIGATION. 121(4). p.1329-1343
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
CELL-CYCLE PROGRESSION, N-TERMINAL KINASE, UBIQUITIN LIGASE COP1, IN-VIVO, TRANSCRIPTIONAL ACTIVITY, PROSTATE-CANCER, TRANSGENIC MICE, BETHESDA PROPOSALS, NEGATIVE REGULATOR, MOUSE DEVELOPMENT
journal title
JOURNAL OF CLINICAL INVESTIGATION
J. Clin. Invest.
volume
121
issue
4
pages
1329 - 1343
Web of Science type
Article
Web of Science id
000289174600017
JCR category
MEDICINE, RESEARCH & EXPERIMENTAL
JCR impact factor
13.069 (2011)
JCR rank
4/109 (2011)
JCR quartile
1 (2011)
ISSN
0021-9738
DOI
10.1172/JCI45784
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1968069
handle
http://hdl.handle.net/1854/LU-1968069
date created
2011-12-15 13:44:45
date last changed
2012-06-26 14:32:30
@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},
  keyword      = {CELL-CYCLE PROGRESSION,N-TERMINAL KINASE,UBIQUITIN LIGASE COP1,IN-VIVO,TRANSCRIPTIONAL ACTIVITY,PROSTATE-CANCER,TRANSGENIC MICE,BETHESDA PROPOSALS,NEGATIVE REGULATOR,MOUSE DEVELOPMENT},
  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},
}

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.