title: Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics.
abstract: In the present study, we compared the dynamics and composition of microtubules in cell lines derived from the human breast adenocarcinoma MCF-7 containing either the wild-type p53 (wt-p53; MN1) or a dominant-negative variant of p53 gene (mut-p53; MDD2). Mut-p53 cells were significantly resistant to the cytotoxicity of the microtubule-targeted drugs (vinca alkaloids and taxanes), as compared with wt-p53 cells. Studies by high-resolution time-lapse fluorescence microscopy in living cells indicated that the dynamics of microtubules of mut-p53 cells were altered in complex ways and were significantly increased as compared with microtubules in wt-p53 cells. The percentage of time microtubules spent in growing and shortening phases increased significantly, their catastrophe frequency increased, and their overall dynamicity increased by 33%. In contrast, their shortening rate and the mean length shortened decreased. Cells containing mut-p53 displayed increased polymerisation of tubulin, increased protein levels of the class IV beta-tubulin isotype, STOP and survivin, and reduced protein levels of class II beta-tubulin isotype, MAP4 and FHIT. We conclude that p53 protein may contribute to the regulation of microtubule composition and function, and that alterations in p53 function may generate complex microtubule-associated mechanisms of resistance to tubulin-binding agents.
authors.affiliation: INSERM 590-Laboratoire de Cytologie Analytique, Faculté de Médécine Rockefeller, Lyon 69373, France. fgalma@rockefeller.univ-lyon1.fr
authors.forename: C M
authors.initials: CM
authors.lastname: Galmarini
authors.forename: K
authors.initials: K
authors.lastname: Kamath
authors.forename: A
authors.initials: A
authors.lastname: Vanier-Viornery
authors.forename: V
authors.initials: V
authors.lastname: Hervieu
authors.forename: E
authors.initials: E
authors.lastname: Peiller
authors.forename: N
authors.initials: N
authors.lastname: Falette
authors.forename: A
authors.initials: A
authors.lastname: Puisieux
authors.forename: M
authors.initials: M
authors.lastname: Ann Jordan
authors.forename: C
authors.initials: C
authors.lastname: Dumontet
mesh_terms: D017766:Acid Anhydride Hydrolases; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D017931:DNA Primers / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D016147:Genes, Tumor Suppressor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D000077022:Survivin; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D000099170:Bis(5'-adenosyl)triphosphatase; C107489:BIRC5 protein, human; C491894:MAP6 protein, human