The role of MAP4 expression in the sensitivity to paclitaxel and resistance to vinca alkaloids in p53 mutant cells.
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.
Zhang
C C
CC
Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Yang
J M
JM
White
E
E
Murphy
M
M
Levine
A
A
Hait
W N
WN
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D018432:Drug Resistance, Multiple; D007668:Kidney; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000187:drug effects*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D011108:Polymers / Q000378:metabolism; D051381:Rats; D011955:Receptors, Drug / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics*; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D008869:Microtubule-Associated Proteins; D011108:Polymers; D011955:Receptors, Drug; D016159:Tumor Suppressor Protein p53; D014750:Vincristine; D014747:Vinblastine; D017239:Paclitaxel