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Vol. 12, Issue 6, 1569-1582, June 2001
and
*Centre de recherche en cancérologie de l'Université
Laval, L'Hôtel-Dieu de Québec, Centre hospitalier
universitaire de Québec, 9 rue McMahon, Québec, Canada G1R
2J6; and The stress-activated protein kinase p38 is often induced by
cytotoxic agents, but its contribution to cell death is ill defined. In
Rat-1 cells, we found a strong correlation between activation of p38
and induction of c-Myc-dependent apoptosis. In cells with deregulated
c-Myc expression but not in control cells,
cis-diamminedichloroplatinum induced p38 activity and
typical features of apoptosis, including internucleosomal DNA
degradation, induction of caspase activities, and both nuclear (nuclear
condensation and fragmentation) and extranuclear (cell blebbing)
morphological alterations. The pan-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 caspase substrates, suggesting that p38 and caspase
activation can contribute distinct features of apoptosis. Accordingly,
we found that cell blebbing was independent of caspase activity and,
rather, depended on p38-sensitive changes in microfilament dynamics
likely mediated by heat shock protein 27 phosphorylation. Furthermore,
p38 activity contributed to both caspase-dependent and
caspase-independent nuclear condensation and fragmentation, suggesting
a role in an early event triggering both mechanisms of apoptosis or
sensitizing the cells to the action of both types of apoptosis
executioners. Inhibiting p38 also resulted in a significant enhancement
in cell survival estimated 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.
Department of Radiation Oncology, Medical
College of Virginia, Virginia Commonwealth University, Richmond,
Virginia 23298-0058
Corresponding author. E-mail
address: jacques.landry{at}med.ulaval.ca
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