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p53 causes drug resistance


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Tumors resistant to (vinca alkaloids and taxanes) may have a p53 mutation. If your tumor does not respond to taxanes consider a p53 test.

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

C M Galmarini1,3, K Kamath2,3, A Vanier-Viornery1, V Hervieu1, E Peiller1, N Falette1, A Puisieux1, M Ann Jordan2 and C Dumontet1

1INSERM 590-Laboratoire de Cytologie Analytique, Faculté de Médécine Rockefeller, Lyon 69373, France

2Department of Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, CA 93106, USA

Correspondence to: Dr CM Galmarini, INSERM 590-Laboratoire de Cytologie Analytique, Faculté de Médécine Rockefeller. 8, Av. Rockefeller-69373 Lyon Cedex 08, France. E-mail: fgalma@rockefeller.univ-lyon1.fr

3Both authors contributed equally to this work.


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 -tubulin isotype, STOP and survivin, and reduced protein levels of class II -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.

British Journal of Cancer (2003) 88, 1793-1799. doi:10.1038/sj.bjc.6600960



protein p53; cytoskeleton; microtubules; drug resistance; antineoplastic agents

Revised 5 February 2003; accepted 13 March 2003

2 June 2003, Volume 88, Number 11, Pages 1793-1799

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