The
Fas receptor mediates a signalling cascade resulting in programmed cell death (apoptosis) within hours of receptor cross-linking. In this study Fas activated the stress-responsive
mitogen-activated protein kinases, p38 and JNK, within 2 h in Jurkat T lymphocytes but not the
mitogen-responsive
kinase ERK1 or pp70S6k. Fas activation of p38 correlated temporally with the onset of apoptosis, and transfection of constitutively active MKK3 (glu), an upstream regulator of p38, potentiated Fas-induced cell death, suggesting a potential involvement of the MKK3/p38 activation pathway in Fas-mediated apoptosis. Fas has been shown to require
ICE (interleukin-1 beta-converting enzyme) family
proteases to induce apoptosis from studies utilizing the
cowpox ICE inhibitor
protein CrmA, the synthetic tetrapeptide
ICE inhibitor
YVAD-CMK, and the tripeptide pan-
ICE inhibitor
Z-VAD-FMK. In this study, crmA antagonized, and
YVAD-CMK and
Z-VAD-FMK completely inhibited, Fas activation of p38
kinase activity, demonstrating that Fas-dependent activation of p38 requires
ICE/CED-3 family members and conversely that the MKK3/p38 activation cascade represents a downstream target for the
ICE/CED-3 family
proteases. Intriguingly, p38 activation by
sorbitol and
etoposide was resistant to
YVAD-CMK and
Z-VAD-FMK, suggesting the existence of an additional mechanism(s) of p38 regulation. The
ICE/CED-3 family-p38 regulatory relationship described in the current work indicates that in addition to the previously described destructive cleavage of substrates such as
poly(ADP ribose) polymerase,
lamins, and topoisomerase, the apoptotic
cysteine proteases also function to regulate stress
kinase signalling cascades.