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Originally published In Press as doi:10.1074/jbc.M203636200 on June 4, 2002

J. Biol. Chem., Vol. 277, Issue 33, 29973-29982, August 16, 2002
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Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor alpha -induced AKT2 through Activation of the NFkappa B Pathway in Human Epithelial Cells*

Zeng-qiang YuanDagger §, Richard I. Feldman||, Mei SunDagger , Nancy E. Olashaw§, Domenico CoppolaDagger §, Gene E. SussmanDagger , Sue A. ShelleyDagger , Santo V. NicosiaDagger , and Jin Q. ChengDagger §**

From the Dagger  Department of Pathology and § Molecular Oncology and Drug Discovery Program, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612 and || Cancer Research Department, Berlex Biosciences, Richmond, California 94804

Previous studies have demonstrated that AKT1 and AKT3 are activated by heat shock and oxidative stress via both phosphatidylinositol 3-kinase-dependent and -independent pathways. However, the activation and role of AKT2 in the stress response have not been fully elucidated. In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor alpha  (TNFalpha ) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UV- and TNFalpha -induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stress- and TNFalpha -induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates Ikappa B kinase alpha . The phosphorylation of Ikappa B kinase alpha  and activation of NFkappa B mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UV- and TNFalpha -induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNFalpha stimulation with an accompanying decreased JNK and p38 activity. These results indicate that activated AKT2 protects epithelial cells from stress- and TNFalpha -induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NFkappa B pathway.

* This work was supported by NCI, National Institutes of Health Grants CA77935 and CA89242 and Department of Defense Grants DAMD17-00-0559 and DAMD 17-01-1-0394.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Predoctoral Fellowship awardee, under Department of Defense Grant DAMD 17-01-1-0397.

** To whom correspondence should be addressed: Dept. of Pathology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, 12901 Bruce B. Downs Blvd., MDC Box 11, Tampa, FL 33612. Tel.: 813-974-8595; Fax: 813-974-5536; E-mail: jcheng@hsc.usf.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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