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Molecular and Cellular Biology, December 2002, p. 8175-8183, Vol. 22, No. 23
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.23.8175-8183.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The p65/RelA Subunit of NF-{kappa}B Suppresses the Sustained, Antiapoptotic Activity of Jun Kinase Induced by Tumor Necrosis Factor

Julie Y. Reuther-Madrid,1,{dagger} David Kashatus,1,2 Shaoqiong Chen,3 Xiong Li,1,{ddagger} John Westwick,4 Roger J. Davis,5 H. Shelton Earp,6,7 Cun-Yu Wang,3 and Albert S. Baldwin Jr.1,2,8*

Lineberger Comprehensive Cancer Center,1 Curriculum in Genetics and Molecular Biology,2 Department of Medicine,6 Department of Pharmacology,7 Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599,8 Laboratory of Molecular Signaling, Department of Biologic and Material Science, University of Michigan, Ann Arbor, Michigan 48109,3 Celgene, San Diego, California, 92121,4 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 016055

Received 16 November 2001/ Returned for modification 31 January 2002/ Accepted 30 August 2002

Tumor necrosis factor (TNF) signaling through the TNF receptors involves the recruitment of key signaling factors, leading to the activation of both the transcription factor NF-{kappa}B and the stress-activated Jun kinase (JNK). In most cells, TNF signaling leads to a rapid and transient increase in JNK activity. However, we show that TNF treatment leads to the sustained activation of JNK in cells that are null for the p65/RelA subunit of NF-{kappa}B as well as in cells expressing the super-repressor form of I{kappa}B. In addition, the data indicate that the ability of p65/RelA to regulate gene expression is required to suppress the persistent activation of JNK. Interestingly, this suppression occurs upstream of JNK, within the signal transduction cascade leading to JNK activation, without affecting the stress-activated kinase p38. Since NF-{kappa}B has previously been shown to be involved in the suppression of TNF-induced apoptosis, we were interested in determining the role of deregulated JNK activity, induced by the loss of NF-{kappa}B, in controlling the cell death response. Through the use of different approaches for inhibition of JNK, we show that the suppression of JNK activity in cells that lack active NF-{kappa}B enhances the apoptotic response to TNF. These data suggest that the activity of JNK in cells blocked for NF-{kappa}B function provides an antiapoptotic signal and explains, at least partly, why a significant number of NF-{kappa}B null cells remain viable following TNF treatment.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, Campus Box 7295, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295. Phone: (919) 966-3652. Fax: (919) 966-0444. E-mail: jhall{at}med.unc.edu.

{dagger} Present address: Fred Hutchinson Cancer Center, Seattle, Wash.

{ddagger} Present address: Monsanto, Inc., St. Louis, Mo.

Molecular and Cellular Biology, December 2002, p. 8175-8183, Vol. 22, No. 23
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.23.8175-8183.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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