Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Apoptosis / physiology
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Caenorhabditis elegans Proteins
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Caspase 1
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Caspases*
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Cysteine Endopeptidases / metabolism*
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Dactinomycin / pharmacology
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Etoposide / pharmacology
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Helminth Proteins / physiology
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Humans
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Imidazoles / pharmacology
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JNK Mitogen-Activated Protein Kinases
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Jurkat Cells
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MAP Kinase Kinase 3
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Mitogen-Activated Protein Kinase Kinases*
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Mitogen-Activated Protein Kinases*
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Protease Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / genetics
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Protein Synthesis Inhibitors / pharmacology
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Protein-Tyrosine Kinases / genetics
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Pyridines / pharmacology
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Serpins / physiology
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Signal Transduction / physiology*
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Sorbitol / pharmacology
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Transcription, Genetic / physiology
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Viral Proteins*
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fas Receptor / physiology*
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p38 Mitogen-Activated Protein Kinases
Substances
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Amino Acid Chloromethyl Ketones
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Caenorhabditis elegans Proteins
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Enzyme Inhibitors
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Helminth Proteins
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Imidazoles
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N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
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Protease Inhibitors
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Protein Synthesis Inhibitors
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Pyridines
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Serpins
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Viral Proteins
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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fas Receptor
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Dactinomycin
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Sorbitol
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Etoposide
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interleukin-1beta-converting enzyme inhibitor
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 3
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MAP2K3 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Caspases
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Cysteine Endopeptidases
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ced-3 protein, C elegans
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Caspase 1
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SB 203580