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The Journal of Immunology, 2000, 164: 1355-1363.
Copyright © 2000 by The American Association of Immunologists

Phosphatidylinositol 3-Kinase as a Mediator of TNF-Induced NF-{kappa}B Activation1

Shrikanth A. G. Reddy, Jianyi H. Huang and Warren S.-L. Liao2

Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030

The activation of transcription factor NF-{kappa}B by TNF involves the stimulation of a novel signaling cascade. In this paper we show that phosphatidylinositol 3-kinase (PI 3-kinase) may play a pivotal role in TNF-mediated activation of NF-{kappa}B-dependent genes. Consistent with its involvement in TNF signaling, PI 3-kinase activities in HepG2 and U937 cells can be stimulated by TNF in a rapid but transient manner through a mechanism that may involve its association with the insulin receptor substrate-1. A dominant-negative mutant of the p85 regulatory subunit of PI 3-kinase, which is a potent inhibitor of PI 3-kinase signaling, effectively blocked the TNF-induced expression of an NF-{kappa}B-dependent reporter gene. Although PI 3-kinase may be required for NF-{kappa}B activation, overexpression of its p110 catalytic subunit alone was unable to induce an NF-{kappa}B/chloramphenicol acetyltransferase (CAT) reporter gene. However, when TNF was added to p110-overexpressing cells, there was a synergistic activation of the NF-{kappa}B/CAT reporter, suggesting that other TNF-inducible signals may cooperate with PI 3-kinase to activate NF-{kappa}B. Consistent with its role in NF-{kappa}B activation, inhibition of PI 3-kinase activity by wortmannin or LY294002 greatly potentiated TNF-induced apoptosis. This TNF/wortmannin-induced apoptosis was markedly prevented in cells overexpressing Rel A. Taken together, our results indicate that a PI 3-kinase-regulated step in TNF-signaling is critical for the expression of NF-{kappa}B-dependent genes.




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