Involvement of p38 in apoptosis-associated membrane blebbing and nuclear condensation

The stress-activated protein kinase p38 is often induced by cytotoxic agent s, but its contribution to cell death is ill defined. In Rat-1 cells, we fo und a strong correlation between activation of p38 and induction of c-Myc-d ependent apoptosis. In cells with deregulated c-Myc expression but not in c ontrol cells, cis-diamminedichloroplatinum. induced p38 activity and typica l features of apoptosis, including internucleosomal DNA degradation, induct ion of caspase activities, and both nuclear (nuclear condensation and fragm entation) and extranuclear (cell blebbing) morphological alterations. The p an-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone did not block p38 activation and the p38 inhibitor SB203580 had no detectable effect on the activation of caspases or the in vivo cleavage of several cas pase substrates, suggesting that p38 and caspase activation can contribute distinct features of apoptosis. Accordingly, we found that cell blebbing wa s independent of caspase activity and, rather, depended on p38-sensitive ch anges in microfilament dynamics likely mediated by heat shock protein 27 ph osphorylation. Furthermore, p38 activity contributed to both caspase-depend ent and caspase-independent nuclear condensation and fragmentation, suggest ing a role in an early event triggering both mechanisms of apoptosis or sen sitizing the cells to the action of both types of apoptosis executioners. I nhibiting p38 also resulted in a significant enhancement in cell survival e stimated by colony formation. This capacity to modulate the sensitivity to apoptosis in cells with deregulated c-Myc expression suggests an important role for p38 in tumor cell killing by chemotherapeutic agents.