Human GTSE-1 regulates p21CIP1/WAF1 stability conferring resistance to paclitaxel treatment

Abstract

p21CIP1/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 p21CIP1/WAF1 levels mediated by the human GTSE-1 (G 2 and S phase-expressed-1) protein. Our results provide evidence that hGTSE-1 protects p21CIP1/WAF1 from proteasome-dependent degradation as part of a functional complex containing the Hsp90-bindingTPR 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-p21CIP1/WAF1 stabilization is clearly involved in the ability of cells to counter-act cytotoxicity induced by the microtubule poison paclitaxel. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.