The role of MAP4 expression in the sensitivity to paclitaxel and resistance to vinca alkaloids in p53 mutant cells

Christine C. Zhang, Jin Ming Yang, Eileen White, Maureen Murphy, Arnold Levine, William N. Hait

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

Abstract

Mutations in p53 change the sensitivity to cancer chemotherapeutic drugs. Whereas many drugs, including the vinca alkaloids, often become less effective when p53 is transcriptionally inactivated, several, most notably paclitaxel, may become more effective. In studying the underlying mechanism(s), we found that increased MAP4 expression, which occurs with transcriptionally silent p53, is associated with increased sensitivity to paclitaxel and decreased sensitivity to vinca alkaloids. Using murine fibroblasts transfected with MAP4, we directly demonstrated that the changes in drug sensitivity were associated with parallel alterations in drug-induced apoptosis and cell-cycle arrest. Immunofluorescent staining of the microtubule network revealed that cells with increased MAP4 expression displayed an increase in polymerized microtubules and an increased binding of fluorsceinated paclitaxel. Since MAP4 stabilizes polymerized microtubules, overexpression of this gene provides a plausible mechanism to explain the altered sensitivity to microtubule-active drugs in the presence of mutant p53.

Original languageEnglish
Pages (from-to)1617-1624
Number of pages8
JournalOncogene
Volume16
Issue number12
DOIs
StatePublished - Mar 26 1998

Bibliographical note

Funding Information:
The authors thank Dr Joanna B Olmsted for the MAP4 monoclonal Ab IF5, Dr Edward M Bonder and Mira F Krendel for advice and expertise with immunfluorescence microscopy. We also thank Dr Steve Ward for helping with the fluorescent microscopy. This work was supported by grants from the Public Health Service including grants CA66077, CA43888, and CA57124 from the National Cancer Institute, a generous grant from The Hyde and Watson Foundation to Dr William N Hait, grant CA53370 from the National Cancer Institute to Dr Eileen White, and grant CA41086 from the National Cancer Institute to Dr Arnold Levine.

Keywords

  • Drug sensitivity
  • MAP4
  • Microtubule polymerization
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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