14-3-3sigma exerts tumor-suppressor activity mediated by regulation of COP1 stability

Cancer Res. 2011 Feb 1;71(3):884-94. doi: 10.1158/0008-5472.CAN-10-2518. Epub 2010 Dec 6.


Constitutive photomorphogenic 1 (COP1) is a p53-targeting E3 ubiquitin ligase that is downregulated by DNA damage through mechanisms that remain obscure. Here, we report that COP1 is not downregulated following DNA damage in 14-3-3σ null cells, implicating 14-3-3σ as a critical regulator in the response of COP1 to DNA damage. We also identified that 14-3-3σ, a p53 target gene product, interacted with COP1 and controlled COP1 protein stability after DNA damage. Mechanistic studies revealed that 14-3-3σ enhanced COP1 self-ubiquitination, thereby preventing COP1-mediated p53 ubiquitination, degradation, and transcriptional repression. In addition, we found that COP1 expression promoted cell proliferation, cell transformation, and tumor progression, manifesting its role in cancer promotion, whereas 14-3-3σ negatively regulated COP1 function and prevented tumor growth in a mouse xenograft model of human cancer. Immunohistochemical analysis of clinical breast and pancreatic cancer specimens demonstrated that COP1 protein levels were inversely correlated with 14-3-3σ protein levels. Together, our findings define a mechanism for posttranslational regulation of COP1 after DNA damage that can explain the correlation between COP1 overexpression and 14-3-3σ downregulation during tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 14-3-3 Proteins / genetics
  • 14-3-3 Proteins / metabolism*
  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Adhesion / physiology
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • DNA Damage
  • Down-Regulation
  • Exonucleases / genetics
  • Exonucleases / metabolism*
  • Exoribonucleases
  • HCT116 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Transfection
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / antagonists & inhibitors
  • Ubiquitin-Protein Ligases / biosynthesis
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • 14-3-3 Proteins
  • Biomarkers, Tumor
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • COP1 protein, human
  • Ubiquitin-Protein Ligases
  • Exonucleases
  • Exoribonucleases
  • SFN protein, human