Cooperative actions of p21WAF1 and p53 induce Slug protein degradation and suppress cell invasion

EMBO Rep. 2014 Oct;15(10):1062-8. doi: 10.15252/embr.201438587. Epub 2014 Aug 20.

Abstract

How the p53 transcription factor/tumor suppressor inhibits cell invasion is poorly understood. We demonstrate that this function of p53 requires its direct interaction with p21(WAF1), a transcriptional target of p53, and that both p21 and p53 bind to Slug, which promotes cell invasion. Functional studies reveal that p21 and p53 cooperate to facilitate Mdm2-dependent Slug degradation and that this p53 function is mimicked by p53(R273H), a mutant lacking trans-activating activity. These actions of p21 and p53 are induced by γ-irradiation of cells and also operate in vivo. This is the first study to elucidate a mechanism involving p53 and p21 cooperation.

Keywords: Cancer; Slug; invasion; p21; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Gamma Rays
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Neoplasm Invasiveness / genetics*
  • Protein Binding / radiation effects
  • Proteolysis / radiation effects
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation / radiation effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2