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/Waf1) expression. Nevertheless, stable expression of U937 cells with a p21(Cip1/WAF1) antisense construct blocked paclitaxel-induced G(2)M 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.
Ahmed
Wesam
W
Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia 23298, USA.
Rahmani
Mohamed
M
Dent
Paul
P
Grant
Steven
S
D016375:Antisense Elements (Genetics); D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D008940:Mitotic Index; D017239:Paclitaxel / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D020298:U937 Cells
D016375:Antisense Elements (Genetics); D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D004318:Doxycycline; D013755:Tetradecanoylphorbol Acetate; D017239:Paclitaxel