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Nuclear receptor CAR represses TNFα-induced cell death by interacting with the anti-apoptotic GADD45B

Yamamoto, Y and Moore, R and Flavell, RA and Lu, B and Negishi, M (2010) Nuclear receptor CAR represses TNFα-induced cell death by interacting with the anti-apoptotic GADD45B. PLoS ONE, 5 (4).

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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 45β (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 α (TNFα)-induced JNK1 phosphorylation as well as cell death. Primary hepatocytes, prepared from Car+/+, Car-/-, Gadd45b+/+ and Gadd45b-/- mice, were treated with TNFα and Actinomycin D to induce phosphorylation of JNK1 and cell death. Cotreatment with the CAR activating ligand TCPOBOP (1,4 bis[2-(3,5-dichloropyridyloxy)]benzene) has resulted in repression of both phosphorylation and cell death in the primary hepatocytes from Car+/+ but not Car2/2mice. Repression by TCPOBOP was not observed in those prepared from Gadd45b-/- mice. In vitro protein-protein interaction and phosphorylation assays have revealed that CAR interacts with MKK7 and represses the MKK7-mediated phosphorylation of JNK1. Conclusions/Significance: CAR can form a protein complex with GADD45B, through which CAR represses MKK7-mediated phosphorylation of JNK1. In addition to activating the Gadd45b gene, CAR may repress death of mouse primary hepatocytes by forming a GADD45B complex and repressing MKK7-mediated phosphorylation of JNK1. The present finding that CAR can repress cell death via its interaction with GADD45B provides an insight for further investigations into the CAR-regulated molecular mechanism by which PB promotes development of HCC.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Yamamoto, Y
Moore, R
Flavell, RA
Lu, Bbinfeng@pitt.eduBINFENG
Negishi, M
Date: 10 September 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0010121
Schools and Programs: School of Medicine > Immunology
Refereed: Yes
MeSH Headings: Animals; Antigens, Differentiation--metabolism; Apoptosis Regulatory Proteins--metabolism; Cell Death; Hepatocytes--cytology; Hepatocytes--metabolism; Liver; MAP Kinase Kinase 7--metabolism; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 8--metabolism; Phenobarbital--pharmacology; Phosphorylation; Receptors, Cytoplasmic and Nuclear--metabolism; Receptors, Cytoplasmic and Nuclear--physiology; Tumor Necrosis Factor-alpha--pharmacology
Other ID: NLM PMC2853562
PubMed Central ID: PMC2853562
PubMed ID: 20404936
Date Deposited: 03 Aug 2012 19:00
Last Modified: 24 Jun 2021 04:55


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