Docetaxel (DOC), a member of the taxane family of anticancer drugs, binds to tubulin and produces unnaturally stable microtubules that induce cell death. DOC is used clinically alone or in combination with other compounds to treat advanced stages of cancer. We have treated the human lung cancer cell lines A549 and H1299 and human cervical cancer HeLa cells with low concentrations of DOC to characterize the response of b-tubulin isotypes and p53 genes. The relationship between p53 function and DOC, acting through a microtubule-based mechanism, was examined. We found that after 18-hr treatment with DOC, b-tubulin gene transcription was enhanced in p53-null H1299 cells but not in A549 cells. Also, p53 RNA was strongly induced in the A549 cells. In addition, b-tubulin levels also increased in the H1299 cells after the DOC treatment. Further demonstrating an association of DOC treatment with p53 and b-tubulin, inhibition of p53 expression by interference RNA in A549 cells showed increasing b-tubulin gene expression with DOC treatment. We also selected a clone from the H1299 cells that stably expressed p53, examined the b-tubulin expression after DOC treatment and found an inhibition of b-tubulin induction in these p53-expressing cells. Our data suggest that the initial response of cells to DOC treatment involves p53; alternatively, in the absence of p53, tubulins may be transactivated. Selection of the DOC-resistant A549 cells showed b-tubulin expression was increased, in contrast to the initial response to the DOC treatment. From the initial and selection responses of b-tubulin in cancer cells, it appears that there is a p53-associated b-tubulin expression as a result of the DOC treatment.