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

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

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Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, International Centre for Genetic Engineering and Biotechnology, Area Science Park, Padriciano 99, 34149 Trieste, Italy.


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.

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