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Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method
16:07

Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method

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

Yukio Yamamoto1, Rick Moore, Richard A Flavell

  • 1Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.

Plos One
|April 21, 2010
PubMed
Abstract

Insights

Phenobarbital (PB) promotes liver cancer by activating the CAR receptor. CAR targets GADD45B to repress cell death, offering new insights into PB-induced hepatocellular carcinoma (HCC) development.

Area of Science:

  • Hepatocellular carcinoma (HCC) research
  • Molecular mechanisms of carcinogenesis
  • Nuclear receptor signaling

Background:

  • Phenobarbital (PB) is a non-genotoxic carcinogen linked to hepatocellular carcinoma (HCC).
  • The Constitutive Active/Androstane Receptor (CAR) is activated by PB and promotes HCC.
  • The precise molecular mechanism of CAR-mediated tumor promotion is not fully understood.

Purpose of the Study:

  • To identify novel CAR targets involved in HCC promotion.
  • To elucidate the mechanism by which CAR represses cell death.
  • To investigate the role of Growth Arrest and DNA Damage-inducible 45beta (GADD45B) in CAR-mediated hepatocarcinogenesis.

Main Methods:

  • Identification of GADD45B as a CAR target gene in mouse liver.
  • Treatment of primary hepatocytes from wild-type and knockout mice with TNFalpha and Actinomycin D.
  • Co-treatment with the CAR activator TCPOBOP.
  • In vitro protein-protein interaction and phosphorylation assays.

Main Results:

  • CAR activation by PB induces GADD45B expression in mouse liver during HCC development.
  • CAR interacts with GADD45B to repress TNFalpha-induced JNK1 phosphorylation and cell death.
  • TCPOBOP repressed JNK1 phosphorylation and cell death in wild-type but not CAR- or GADD45B-deficient hepatocytes.
  • CAR directly interacts with MKK7, inhibiting JNK1 phosphorylation.

Conclusions:

  • CAR forms a protein complex with GADD45B to inhibit MKK7-mediated JNK1 phosphorylation.
  • CAR represses primary hepatocyte death through GADD45B complex formation and MKK7 inhibition.
  • This study provides novel insights into the CAR-regulated molecular mechanisms underlying PB-induced HCC.

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