title: Human GTSE-1 regulates p21(CIP1/WAF1) stability conferring resistance to paclitaxel treatment.
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.
authors.affiliation: Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, International Centre for Genetic Engineering and Biotechnology, Area Science Park, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Débora Rosa
authors.initials: DR
authors.lastname: Bublik
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Scolz
authors.forename: Gianluca
authors.initials: G
authors.lastname: Triolo
authors.forename: Martín
authors.initials: M
authors.lastname: Monte
authors.forename: Claudio
authors.initials: C
authors.lastname: Schneider
mesh_terms: 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
chemical_list: 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