COP1 enhances ubiquitin-mediated degradation of p27Kip1 to promote cancer cell growth

Oncotarget. 2015 Aug 14;6(23):19721-34. doi: 10.18632/oncotarget.3821.

Abstract

p27 is a critical CDK inhibitor involved in cell cycle regulation, and its stability is critical for cell proliferation. Constitutive photomorphogenic 1 (COP1) is a RING-containing E3 ubiquitin ligase involved in regulating important target proteins for cell growth, but its biological activity in cell cycle progression is not well characterized. Here, we report that p27Kip1 levels are accumulated in G1 phase, with concurrent reduction of COP1 levels. Mechanistic studies show that COP1 directly interacts with p27 through a VP motif on p27 and functions as an E3 ligase of p27 to accelerate the ubiquitin-mediated degradation of p27. Also, COP1-p27 axis deregulation is involved in tumorigenesis. These findings define a new mechanism for posttranslational regulation of p27 and provide insight into the characteristics of COP1-overexpressing cancers.

Keywords: COP1; cell cycle; p27; ubiquitination.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Cell Cycle
  • Cell Proliferation*
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice, Nude
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational*
  • Proteolysis*
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tumor Burden*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • CDKN1B protein, human
  • Cyclin-Dependent Kinase Inhibitor p27
  • COP1 protein, human
  • Ubiquitin-Protein Ligases