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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-{kappa}B-Mediated Inhibition of c-Jun N-Terminal Kinase Activation Contributes to Tumor Necrosis Factor Alpha-Induced Apoptosis

Fangming Tang, Guilin Tang, Jialing Xiang, Qing Dai, Marsha R. Rosner, and Anning Lin*

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-{alpha}) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-{alpha} exerts its biological activities by activating multiple signaling pathways, including I{kappa}B kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-{kappa}B, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-{kappa}B pathway, TNF-{alpha} 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-{alpha}-induced apoptosis is incompletely understood. Here we report that in TNF-{alpha}-sensitive cells activation of the IKK/NF-{kappa}B pathway fails to block TNF-{alpha}-induced apoptosis, although its inactivation still promotes TNF-{alpha}-induced apoptosis. Interestingly, TNF-{alpha}-induced apoptosis is suppressed by inhibition of the JNK pathway but promoted by its activation. Furthermore, activation of JNK by TNF-{alpha} was transient in TNF-{alpha}-insensitive cells but prolonged in sensitive cells. Conversion of JNK activation from prolonged to transient suppressed TNF-{alpha}-induced apoptosis. Thus, absence of NF-{kappa}B-mediated inhibition of JNK activation contributes to TNF-{alpha}-induced apoptosis.

* Corresponding author. Mailing address: Ben May Institute for Cancer Research, University of Chicago, 5841 S. Maryland Ave., MC 60627, Chicago, IL 60637. Phone: (773) 753-1408. Fax: (773) 702-6260. E-mail: alin{at}huggins.bsd.uchicago.edu.

Molecular and Cellular Biology, December 2002, p. 8571-8579, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8571-8579.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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