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PMID: 10794718 Published · ppublish English Journal Article

JNK (c-Jun N-terminal kinase) and p38 activation in receptor-mediated and chemically-induced apoptosis of T-cells: differential requirements for caspase activation.

The Biochemical journal ·Vol. 348 Pt 1 ·2000-05-15 ·Pages 93-101

MacFarlane M, Cohen GM, Dickens M

Abstract

Activation of the stress-activated mitogen-activated protein kinases (MAP kinases), c-Jun N-terminal kinase (JNK) and p38, is necessary for the induction of apoptosis in neuronal cells; however, in other cell types their involvement may be stimulus-dependent. In the present study we investigate the activation of JNK and p38 in a single non-neuronal cell type, undergoing receptor-mediated (tumour necrosis factor-related apoptosis-inducing ligand and CD95) or chemically-induced (lactacystin) apoptosis. In Jurkat T-cells, receptor-mediated and chemically-induced apoptosis resulted in a time-dependent activation of the initiator caspases-8 and -9, respectively. Both types of stimuli resulted in a significant activation of JNK and p38, which closely paralleled the time-dependent induction of apoptosis. The caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone (z-VAD.FMK) inhibited receptor-mediated apoptosis and suppressed JNK and p38 activation. In contrast, inhibition of lactacystin-induced apoptosis with z-VAD.FMK, as assessed by phosphatidylserine exposure and poly(ADP-ribose) polymerase cleavage, did not inhibit activation of JNK or p38, demonstrating that during chemically-induced apoptosis, activation of JNK and p38 is independent of effector caspases. The role of p38 in apoptosis was assessed using the specific p38 inhibitor, SB203580. No effect on the induction of apoptosis or caspase activation was observed, although activation of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK-2), an immediate downstream target of p38, was inhibited. Therefore neither p38 activation nor activation of MAPKAPK-2 is critical for induction of either receptor- or chemically-induced apoptosis. Thus, within a single cell type, (1) the mechanism of p38 and JNK activation during apoptosis is stimulus-dependent and (2) activation of the p38 pathway is not required for caspase activation or apoptosis, assessed by phosphatidylserine exposure, but may still be required to elicit other features of the apoptotic phenotype.

MeSH Terms
Acetylcysteine/analogs & derivatives Amino Acid Chloromethyl Ketones/pharmacology Apoptosis Apoptosis Regulatory Proteins Caspase 3 Caspase 8 Caspase 9 Caspase Inhibitors Caspases/metabolism Cysteine Proteinase Inhibitors/pharmacology Enzyme Activation Enzyme Inhibitors/pharmacology Humans Imidazoles/pharmacology Intracellular Signaling Peptides and Proteins JNK Mitogen-Activated Protein Kinases Jurkat Cells Membrane Glycoproteins/physiology Mitogen-Activated Protein Kinases/metabolism Protein Serine-Threonine Kinases/metabolism Pyridines/pharmacology T-Lymphocytes/enzymology,physiology TNF-Related Apoptosis-Inducing Ligand Time Factors Tumor Necrosis Factor-alpha/physiology fas Receptor/physiology p38 Mitogen-Activated Protein Kinases
Chemicals
Amino Acid Chloromethyl Ketones Apoptosis Regulatory Proteins Caspase Inhibitors Cysteine Proteinase Inhibitors Enzyme Inhibitors Imidazoles Intracellular Signaling Peptides and Proteins Membrane Glycoproteins Pyridines TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human Tumor Necrosis Factor-alpha benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone fas Receptor lactacystin MAP-kinase-activated kinase 2 Protein Serine-Threonine Kinases JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases CASP3 protein, human CASP8 protein, human CASP9 protein, human Caspase 3 Caspase 8 Caspase 9 Caspases SB 203580 Acetylcysteine
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
MacFarlane M
Medical Research Council Toxicology Unit, University of Leicester, UK.
Cohen G M
Dickens M
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
Published
2000-05-15
Pages
93-101
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1221040
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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