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B Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-
-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation1
* First Department of Internal Medicine, and
Department of Biochemistry, Gifu University School of Medicine, Tsukasamachi, Gifu, Japan;
Departments of Medicine, Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599; and
Gifu International Institute of Biotechnology, Mitake, Gifu, Japan
Using a cDNA microarray analysis, we identified x-ray-inducible immediate early response factor-1 (IEX-1) as a proapoptotic gene which was induced by TNF-
and also depend on NF-
B activation in Hc human hepatocytes. In these cells only the original form of IEX-1, termed IEX-1S, but not its longer transcript IEX-1L, was expressed. Overexpression of IEX-1S resulted in promotion of TNF--induced apoptosis in Hc cells expressing a mutant form of IB. This proapoptotic action can be explained by its inhibitory findings on survival signals; inhibition of TNF--induced activation and expression of phosphatidylinositol 3-kinase (PI3K)/Akt, and also blockage of expression of Mcl-1, an antiapoptotic Bcl-2 family member which is located downstream of Akt, was inhibited by IEX-1S. LY 294002, an inhibitor of PI3K, increased IEX-1S expression induced by TNF- and accelerated TNF--induced apoptosis in IB-treated Hc cells. Overexpression of the dominant-negative Akt enhanced, but the constitutively active Akt suppressed, TNF--induced IEX-1S expression, suggesting that PI3K/Akt negatively regulated IEX-1S expression. These results demonstrate that NF-B-dependent recruitment of IEX-1S may play a proapoptotic role in TNF--stimulated hepatocytes through blockage of the PI3K/Akt pathway. Moreover, the reciprocal cross-talk between IEX-1S and PI3K/Akt may closely be involved in the regulation of TNF--induced hepatocyte apoptosis.
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