Journal of Biological Chemistry
Volume 277, Issue 33, 16 August 2002, Pages 29973-29983
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MECHANISMS OF SIGNAL TRANSDUCTION
Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor α-induced AKT2 through Activation of the NFκB Pathway in Human Epithelial Cells*

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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 α (TNFα) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UV- and TNFα-induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stress- and TNFα-induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates IκB kinase α. The phosphorylation of IκB kinase α and activation of NFκB mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UV- and TNFα-induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNFα stimulation with an accompanying decreased JNK and p38 activity. These results indicate that activated AKT2 protects epithelial cells from stress- and TNFα-induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NFκB pathway.

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Published, JBC Papers in Press, June 4, 2002, DOI 10.1074/jbc.M203636200

*

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.