The activation of the extracellular signal-regulated kinases (ERKs) by tumour necrosis factor-α (TNF) receptors (TNFRs) is an integral part of the cytokine's pleiotropic cellular responses. Here we report differences in the caspase sensitivity and TNFR subtype activation of members of the ERK family. Inhibition in HeLa cells of caspase function by pharmacological inhibitors or the expression of CrmA (cytokine response modifier A), a viral modifier protein, blocks TNF-induced apoptosis or caspase-dependent protein kinase Cδ and poly(ADP-ribose) polymerase protein degradation. TNFR1- or TNFR2-stimulated c-Jun N-terminal kinase (JNK) activity was attenuated in cells in which caspase activity was inhibited either by pharmacological blockers or CrmA expression. Both TNFR1- and TNFR2-stimulated JNK activity was caspase-sensitive; however, only TNFR1 was capable of stimulating p42/44 mitogen-activated protein kinase (MAPK) and p38 MAPK activities. TNFR1-stimulated p42/44 MAPK and p38 MAPK activities were insensitive to pharmacological caspase inhibition or CrmA. These findings were supported when measuring TNF-induced cytosolic phospholipase A2 activation, which is a downstream target for MAPK and p38 MAPK. Profiling caspase enzymes activated by TNF in HeLa cells showed sequential caspase-8, −3, −7, −6 and −9 activation, with their inhibition characteristics suggesting a role for caspase-3 and/or caspase-6 in modulating JNK activity. Taken together these results show delineated ERK-activation pathways employed by TNFR subtypes.
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August 2002
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Research Article|
August 15 2002
Tumour necrosis factor-induced activation of c-Jun N-terminal kinase is sensitive to caspase-dependent modulation while activation of mitogen-activated protein kinase (MAPK) or p38 MAPK is not
Ahmed A.A. MOHAMED;
Ahmed A.A. MOHAMED
∗Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K.
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Orla J. JUPP;
Orla J. JUPP
∗Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K.
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Helen M. ANDERSON;
Helen M. ANDERSON
∗Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K.
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Alison F. LITTLEJOHN;
Alison F. LITTLEJOHN
∗Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K.
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Peter VANDENABEELE;
Peter VANDENABEELE
†Molecular Signalling and Cell Death Unit, Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, University of Gent, Ledeganckstraat 35, B-9000 Gent, Belgium
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David J. MacEWAN
David J. MacEWAN
1
∗Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K.
1To whom correspondence should be addressed (e-mail david.macewan@abdn.ac.uk).
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Publisher: Portland Press Ltd
Received:
April 04 2002
Revision Received:
April 30 2002
Accepted:
May 08 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 145–155.
Article history
Received:
April 04 2002
Revision Received:
April 30 2002
Accepted:
May 08 2002
Citation
Ahmed A.A. MOHAMED, Orla J. JUPP, Helen M. ANDERSON, Alison F. LITTLEJOHN, Peter VANDENABEELE, David J. MacEWAN; Tumour necrosis factor-induced activation of c-Jun N-terminal kinase is sensitive to caspase-dependent modulation while activation of mitogen-activated protein kinase (MAPK) or p38 MAPK is not. Biochem J 15 August 2002; 366 (1): 145–155. doi: https://doi.org/10.1042/bj20020527
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