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Molecular and Cellular Biology, December 2002, p. 8571-8579, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8571-8579.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Absence of NF-B-Mediated Inhibition of c-Jun N-Terminal Kinase Activation Contributes to Tumor Necrosis Factor Alpha-Induced Apoptosis

Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637

Received 15 January 2002/ Returned for modification 6 March 2002/ Accepted 27 September 2002

The proinflammatory cytokine tumor necrosis factor alpha (TNF-) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF- exerts its biological activities by activating multiple signaling pathways, including IB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-B, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-B pathway, TNF- is able to induce apoptosis in cells sensitive to it, such as human breast carcinoma MCF-7 and mouse fibroblast LM cells. The molecular mechanism underlying TNF--induced apoptosis is incompletely understood. Here we report that in TNF--sensitive cells activation of the IKK/NF-B pathway fails to block TNF--induced apoptosis, although its inactivation still promotes TNF--induced apoptosis. Interestingly, TNF--induced apoptosis is suppressed by inhibition of the JNK pathway but promoted by its activation. Furthermore, activation of JNK by TNF- was transient in TNF--insensitive cells but prolonged in sensitive cells. Conversion of JNK activation from prolonged to transient suppressed TNF--induced apoptosis. Thus, absence of NF-B-mediated inhibition of JNK activation contributes to TNF--induced apoptosis.

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