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 dru gs, Whereas many drugs, including the vinca alkaloids, often become le ss effective when p53 is transcriptionally inactivated, several, most notably paclitaxel, may become more effective, In studying the underly ing mechanism(s), we found that increased MAP4 expression, which occur s with transcriptionally silent p53, is associated with increased sens itivity to paclitaxel and decreased sensitivity to vinca alkaloids, Us ing murine fibroblasts transfected with MAP4, we directly demonstrated that the changes in drug sensitivity were associated with parallel al terations in drug-induced apoptosis and cell-cycle arrest, Immunofluor escent staining of the microtubule network revealed that cells with in creased MAP4 expression displayed an increase in polymerized microtubu les and an increased binding of fluorsceinated paclitaxel, Since MAP4 stabilizes polymerized microtubules, overexpression of this gene provi des a plausible mechanism to explain the altered sensitivity to microt ubule-active drugs in the presence of mutant p53.