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Evidence of a functional role for the cyclin-dependent kinase inhibitor p21(WAF1/CIP1/MDA6) in the reciprocal regulation of PKC activator-induced apoptosis and differentation in human myelomonocytic leukemia cells.

The functional role of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in leukemic cell G1 arrest, differentiation, and apoptosis induced by two PKC activators (PMA and bryostatin 1) was examined using antisense-expressing lines [U937/p21AS(F4) and U937/p21AS(B8)]. Following incubation with 10 nM PMA (24 h), antisense-expressing cells displayed induction of p27(KIP1) but not of p21, whereas empty vector-containing cells (U937/pREP4) exhibited induction of both p21 and p27. Antisense-expressing cells were impaired in G1 arrest, dephosphorylation of the retinoblastoma protein, dephosphorylation and reduction in activity of cyclin-dependent kinase 2, and acquisition of differentiated features (e.g., plastic adherence). Bryostatin 1 induced p27 but not p21 in control cells and was less effective than PMA in initiating G1 arrest and related events. Nevertheless, disruption of p21 expression abrogated the effects of bryostatin 1 on cell cycle arrest and cellular maturation. Dysregulation of p21 did not, however, modify PMA- or bryostatin 1-mediated down-regulation of c-Myc protein. Unexpectedly, disruption of p21 failed to attenuate the net reduction in viable cell number following PMA or bryostatin 1 treatment inasmuch as impaired differentiation was accompanied by a lowered threshold for PMA- and bryostatin 1-induced apoptosis. Inhibition of p21 expression also promoted PMA- and bryostatin 1-mediated loss of mitochondrial transmembrane potential (DeltaPsim ) and release of cytochrome c into the cytosol. Together, these findings demonstrate a critical functional role for p21 in regulating myelomonocytic leukemic cell G1 arrest and differentiation following exposure to two PKC activators exhibiting disparate patterns of activity. They also suggest that following treatment with these agents, dysregulation of p21 prevents leukemic cells from engaging a normal differentiation program through a c-Myc-independent mechanism, and instead directs cells along an apoptotic pathway.