P. Juo et al., FAS ACTIVATION OF THE P38 MITOGEN-ACTIVATED PROTEIN-KINASE SIGNALING PATHWAY REQUIRES ICE CED-3 FAMILY PROTEASES/, Molecular and cellular biology, 17(1), 1997, pp. 24-35
The Fas receptor mediates a signalling cascade resulting in programmed
cell death (apoptosis) within hours of receptor cross-linking. In thi
s study Fas activated the stress-responsive mitogen activated protein
kinases, p38 and JNK within 2 h in Jurkat T lymphocytes but not the mi
togen-responsive kinase ERK1 or pp70(S6k). Fas activation of p38 corre
lated temporally with the onset of apoptosis, and transfection of cons
titutively active MKK3(glu), an upstream regulator of p38. potentiated
Fas-induced cell death, suggesting a potential involvement of the MKK
3/p38 activation pathway in Fas-mediated apoptosis. Fas has been shown
to require ICE (interleukin-1 beta-converting enzyme) family protease
s to induce apoptosis from studies utilizing the cowpox ICE inhibitor
protein CrmA, the synthetic tetrapeptide ICE inhibitor YVAD-CMK and th
e tripeptide yen-ICE inhibitor Z-VAD-FMK. In this study, crmA antagoni
zed, and YVAD-CMK and Z-VAD-FMK completely inhibited, Fas activation o
f 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 f
amily proteases. Intriguingly, p38 activation hv sorbitol and etoposid
e 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 substr
ates such as poly(ADP ribose) polymerase, lamins, and topoisomerase, t
he apoptotic cysteine proteases also function to regulate stress kinas
e signalling cascades.