Human GTSE-1 regulates p21(CIP1/WAF1) stability conferring resistance to paclitaxel treatment.
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.
Bublik
Débora Rosa
DR
Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, International Centre for Genetic Engineering and Biotechnology, Area Science Park, Padriciano 99, 34149 Trieste, Italy.
Scolz
Massimiliano
M
Triolo
Gianluca
G
Monte
Martín
M
Schneider
Claudio
C
D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020104:Immunophilins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D022021:Tacrolimus Binding Proteins; D050257:Tubulin Modulators / Q000494:pharmacology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C400101:FKBPL protein, human; C115080:GTSE1 protein, human; D018841:HSP90 Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D050257:Tubulin Modulators; D046988:Proteasome Endopeptidase Complex; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D017239:Paclitaxel