PMID- 20404936
OWN - NLM
STAT- MEDLINE
DCOM- 20110616
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 4
DP  - 2010 Apr 12
TI  - Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with 
      the anti-apoptotic GADD45B.
PG  - e10121
LID - 10.1371/journal.pone.0010121 [doi]
LID - e10121
AB  - 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 45beta (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 
      alpha ( TNFalpha)-induced JNK1 phosphorylation as well as cell death. Primary 
      hepatocytes, prepared from Car(+/+), Car(-/-), Gadd45b(+/+) and Gadd45b(-/-) 
      mice, were treated with TNFalpha and Actinomycin D to induce phosphorylation of 
      JNK1 and cell death. Co-treatment 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 
      Car(-/-) mice. 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.
FAU - Yamamoto, Yukio
AU  - Yamamoto Y
AD  - 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.
FAU - Moore, Rick
AU  - Moore R
FAU - Flavell, Richard A
AU  - Flavell RA
FAU - Lu, Binfeng
AU  - Lu B
FAU - Negishi, Masahiko
AU  - Negishi M
LA  - eng
GR  - Z01 ES071005/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20100412
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antigens, Differentiation)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Constitutive Androstane Receptor)
RN  - 0 (Gadd45b protein, mouse)
RN  - 0 (Nr1i3 protein, mouse)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 7)
RN  - YQE403BP4D (Phenobarbital)
SB  - IM
MH  - Animals
MH  - Antigens, Differentiation/*metabolism
MH  - Apoptosis Regulatory Proteins/*metabolism
MH  - Cell Death
MH  - Constitutive Androstane Receptor
MH  - Hepatocytes/*cytology/metabolism
MH  - Liver
MH  - MAP Kinase Kinase 7/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Mitogen-Activated Protein Kinase 8/*metabolism
MH  - Phenobarbital/pharmacology
MH  - Phosphorylation
MH  - Receptors, Cytoplasmic and Nuclear/metabolism/*physiology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
PMC - PMC2853562
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/04/21 06:00
MHDA- 2011/06/17 06:00
PMCR- 2010/04/12
CRDT- 2010/04/21 06:00
PHST- 2010/01/27 00:00 [received]
PHST- 2010/03/15 00:00 [accepted]
PHST- 2010/04/21 06:00 [entrez]
PHST- 2010/04/21 06:00 [pubmed]
PHST- 2011/06/17 06:00 [medline]
PHST- 2010/04/12 00:00 [pmc-release]
AID - 10-PONE-RA-15885R1 [pii]
AID - 10.1371/journal.pone.0010121 [doi]
PST - epublish
SO  - PLoS One. 2010 Apr 12;5(4):e10121. doi: 10.1371/journal.pone.0010121.