X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase1 (JNK1) activation by transforming growth factor-beta 1 (TGF-beta 1) through ubiquitin-mediated proteosomal degradation of the TGF-beta 1-activated kinase1 (TAK1)

doi:10.1074/jbc.M505671200

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Papers In Press, published online ahead of print September 12, 2005
J. Biol. Chem, 10.1074/jbc.M505671200
Submitted on May 24, 2005
Accepted on September 12, 2005

X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase1 (JNK1) activation by transforming growth factor- $beta$ 1 (TGF- $beta$ 1) through ubiquitin-mediated proteosomal degradation of the TGF- $beta$ 1-activated kinase1 (TAK1)

Swayamjot Kaur, Fang Wang, Manickam Venkatraman, and Marcello Arsura

Department of Pharmacology, University of Tennessee, Memphis, TN 38163

Corresponding Author: marsura{at}utmem.edu

Active NF-kappaB renders malignant hepatocytes refractory to the growth inhibitory and pro-apoptotic properties of TGF-beta1. NF-kappaB counteracts TGF-beta1-induced apoptosis through upregulation of downstream target genes, such as XIAP and Bcl-XL, which in turn inhibit the intrinsic pathway of apoptosis. In addition, induction of NF-kB by TGF-beta1 inhibits JNK signaling thereby attenuating TGF-beta1-induced cell death of normal hepatocytes. However, the mechanism involved in the negative crosstalk between the NF-kappaB and JNK pathways during TGF-beta1 signaling has not been determined. In this study, we have identified the XIAP gene as one of the critical mediators of NF-kappaB-mediated suppression of JNK signaling. We show that NF-kappaB plays a role in the upregulation of XIAP gene expression in response to TGF-beta1 treatment and forms a TGF-beta1-inducible complex with TAK1. Furthermore, we show that the RING domain of XIAP mediates TAK1 polyubiquitination, which then targets this molecule for proteosomal degradation. Downregulation of TAK1 protein expression inhibits TGF-beta1-mediated activation of JNK and apoptosis. Conversely, silencing of XIAP promotes persistent JNK activation and potentiates TGF-beta1-induced apoptosis. Collectively, our findings identify a novel mechanism for the regulation of JNK activity by NF-kappaB during TGF-beta1 signaling and raise the possibility that pharmacologic inhibition of the NF-kappaB/ XIAP signaling pathway might selectively abolish the pro-oncogenic activity of TGF-beta1 in advanced HCCs without affecting the pro-apoptotic effects of TGF-beta1 involved in normal liver homeostasis.

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X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase1 (JNK1) activation by transforming growth factor-1 (TGF-1) through ubiquitin-mediated proteosomal degradation of the TGF-1-activated kinase1 (TAK1)

X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase1 (JNK1) activation by transforming growth factor- $beta$ 1 (TGF- $beta$ 1) through ubiquitin-mediated proteosomal degradation of the TGF- $beta$ 1-activated kinase1 (TAK1)