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Vinblastine and paclitaxel (Taxol) are widely used chemotherapeutic drugs that inhibit the normal function of microtubules causing mitotic arrest and cell death. Despite these similarities, the signaling pathways that mediate and regulate cell death induced by these agents remain incompletely understood. The purpose of this study was to directly compare the two drugs in terms of their ability to activate components of the c-Jun N-terminal protein kinase (JNK) pathway, and to establish the importance of these signaling events in apoptosis induced by these agents. We show that both drugs induce mitotic arrest and subsequent apoptotic cell death with highly similar kinetics and that both activate JNK and induce c-Jun protein and c-jun mRNA expression. Surprisingly, vinblastine induced c-Jun phosphorylation and c-jun transcriptional activation, although Taxol failed to do so. However, inhibition of JNK or an absence of JNK protected against both vinblastine- and Taxol-induced cell death. These results suggest that although JNK activation plays an important role in cell death induced by both agents, vinblastine and Taxol differ markedly with respect to signaling downstream of JNK, with AP-1-dependent and -independent mechanisms, respectively. In addition, these results show, contrary to popular belief, that JNK activation is not necessarily accompanied by c-Jun activation, and thus c-Jun is not an obligate substrate of JNK.