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

J Clin Invest. 2011 Apr;121(4):1329-43. doi: 10.1172/JCI45784. Epub 2011 Mar 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Proliferation
  • Female
  • Heterozygote
  • Humans
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Neoplasms / etiology
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Pregnancy
  • Protein Stability
  • RNA, Small Interfering / genetics
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Nuclear Proteins
  • RNA, Small Interfering
  • Transcription Factor AP-1
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • COP1 protein, human
  • COP1 protein, mouse
  • Ubiquitin-Protein Ligases
  • JNK Mitogen-Activated Protein Kinases