The cyclin-dependent kinase inhibitor p21^CIP1/WAF1 blocks paclitaxel-induced G₂M arrest and attenuates mitochondrial injury and apoptosis in p53-null human leukemia cells

The functional significance of the cyclin-dependent kinase inhibitor (CDKI) p21^Cip1/WAF1 in paclitaxel-mediated lethality was examined in p53-null human leukemia cells (U937 and Jurkat). In these cells, paclitaxel exposure failed to induce p21^CiP1/Wof1 expression. Nevertheless, stable expression of U937 cells with a p21^Cip1/WAF1 antisense construct blocked paclitaxel-induced G₂M arrest and increased mitochondrial injury, caspase activation, apoptosis, and loss of clonogenic potential. Consistent with these results, enforced expression of p21 ^Cip1/WAF1 in Jurkat cells increased the percentage of cells arrested in G₂M and attenuated paclitaxel-mediated mitochondrial injury and apoptosis. Unexpectedly, enforced expression of p21^CiP1/WAF1 diminished paclitaxel-mediated inactivation of ERK, and reduced paclitaxel-induced activation of JNK as well as Bcl-2 phosphorylation. Together, these findings suggest that p21^Cip1/WAF1 partially protects p53-null human leukemia cells from paclitaxel-mediated lethality, and raise the possibility that p21^CiP1/WAF1-associated perturbations in signal transduction pathways as well as Bcl-2 phosphorylation status may play a role in this phenomenon.