nuclear receptor car represses tnfα-induced cell death by interacting with the anti-apoptotic gadd45b核受体汽车压制tnfα-induced细胞死亡与抗凋亡gadd45b交互.pdfVIP

Nuclear Receptor CAR Represses TNFa-Induced Cell Death by Interacting with the Anti-Apoptotic GADD45B 1¤ 1 2 3 1 Yukio Yamamoto , Rick Moore , Richard A. Flavell , Binfeng Lu , Masahiko Negishi * 1 Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America, 2 Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America, 3 Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America Abstract Background: Phenobarbital (PB) is the most well-known among numerous non-genotoxic carcinogens that cause the development of hepatocellular carcinoma (HCC). PB activates nuclear xenobiotic receptor Constitutive Active/Androstane Receptor (CAR; NR1I3) and this activation is shown to determine PB promotion of HCC in mice. The molecular mechanism of CAR-mediated tumor promotion, however, remains elusive at the present time. Here we have identified Growth Arrest and DNA Damage-inducible 45b (GADD45B) as a novel CAR target, through which CAR represses cell death. Methodology/Principal Findings: PB activation of nuclear xenobiotic receptor CAR is found to induce the Gadd45b gene in mouse liver throughout the development of HCC as well as in liver tumors. Given the known function of GADD45B as a factor that represses Mitogen-activated protein Kinase Kinase 7 - c-Jun N-terminal Kinase (MKK7-JNK) pathway-mediated apoptosis, we have now demonstrated that CAR interacts with GADD45B to repress Tumor Necrosis Factor a ( TNFa)- induced JNK1 phosphorylation as well as cell death. Primary hepato