Human GTSE-1 regulates p21(CIP1/WAF1) stability conferring resistance to paclitaxel treatment

J Biol Chem. 2010 Feb 19;285(8):5274-81. doi: 10.1074/jbc.M109.045948. Epub 2009 Dec 14.

Abstract

p21(CIP1/WAF1) belongs to the CIP/KIP family of Cdk inhibitors, and its expression is tightly controlled during the cell cycle, mainly by transcriptional and post-translational mechanisms. Fine regulation of p21(CIP1/WAF1) levels is critical for cell cycle control and for cellular response to stress. In the present work, we describe a novel mechanism to modulate p21(CIP1/WAF1) levels mediated by the human GTSE-1 (G(2) and S phase-expressed-1) protein. Our results provide evidence that hGTSE-1 protects p21(CIP1/WAF1) from proteasome-dependent degradation as part of a functional complex containing the Hsp90-binding TPR protein WISp39. We further show that the hGTSE-1 N-terminal portion is sufficient for p21(CIP1/WAF1) binding and stabilization. Finally, we demonstrate that hGTSE-1 mediated-p21(CIP1/WAF1) stabilization is clearly involved in the ability of cells to counteract cytotoxicity induced by the microtubule poison paclitaxel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Drug Resistance / drug effects*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Immunophilins / genetics
  • Immunophilins / metabolism
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Paclitaxel / pharmacology*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / drug effects
  • Protein Stability / drug effects
  • Tacrolimus Binding Proteins
  • Tubulin Modulators / pharmacology

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • FKBPL protein, human
  • GTSE1 protein, human
  • HSP90 Heat-Shock Proteins
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • Tubulin Modulators
  • Proteasome Endopeptidase Complex
  • Tacrolimus Binding Proteins
  • Immunophilins
  • Paclitaxel