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J. Biol. Chem., Vol. 280, Issue 46, 38599-38608, November 18, 2005

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X-linked Inhibitor of Apoptosis (XIAP) Inhibits c-Jun N-terminal Kinase 1 (JNK1) Activation by Transforming Growth Factor 1 (TGF-1) through Ubiquitin-mediated Proteosomal Degradation of the TGF-1-activated Kinase 1 (TAK1)^*

From the Department of Pharmacology, University of Tennessee Cancer Institute (UTCI), University of Tennessee Health Science Center, College of Medicine, University of Tennessee, Memphis, Tennessee 38163

Active NF-B renders malignant hepatocytes refractory to the growth inhibitory and pro-apoptotic properties of transforming growth factor1 (TGF-1). NF-B counteracts TGF-1-induced apoptosis through up-regulation of downstream target genes, such as XIAP and Bcl-X_L, which in turn inhibit the intrinsic pathway of apoptosis. In addition, induction of NF-B by TGF-1 inhibits JNK signaling, thereby attenuating TGF-1-induced cell death of normal hepatocytes. However, the mechanism involved in the negative cross-talk between the NF-B and JNK pathways during TGF-1 signaling has not been determined. In this study, we have identified the XIAP gene as one of the critical mediators of NF-B-mediated suppression of JNK signaling. We show that NF-B plays a role in the up-regulation of XIAP gene expression in response to TGF-1 treatment and forms a TGF-1-inducible complex with TAK1. Furthermore, we show that the RING domain of XIAP mediates TAK1 polyubiquitination, which then targets this molecule for proteosomal degradation. Down-regulation of TAK1 protein expression inhibits TGF-1-mediated activation of JNK and apoptosis. Conversely, silencing of XIAP promotes persistent JNK activation and potentiates TGF-1-induced apoptosis. Collectively, our findings identify a novel mechanism for the regulation of JNK activity by NF-B during TGF-1 signaling and raise the possibility that pharmacologic inhibition of the NF-B/XIAP signaling pathway might selectively abolish the pro-oncogenic activity of TGF-1 in advanced hepatocellular carcinomas (HCCs) without affecting the pro-apoptotic effects of TGF-1 involved in normal liver homeostasis.

Received for publication, May 24, 2005 , and in revised form, August 25, 2005.

^* This work was supported by National Institutes of Health Grant CA78616 (to M. A.) and, in part, by American Cancer Society Grant RSG-02-255-01-TBE (to M. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, University of Tennessee College of Medicine, 874 Union Ave., Memphis TN 38163. Tel.: 901-448-1733; Fax: 901-448-7206; E-mail: marsura{at}utmem.edu.

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