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Molecular Pharmacology

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Extracellular Signal-Regulated Kinase Is an Endogenous Signal Retaining the Nuclear Constitutive Active/Androstane Receptor (CAR) in the Cytoplasm of Mouse Primary Hepatocytes

Chika Koike, Rick Moore and Masahiko Negishi
Molecular Pharmacology May 2007, 71 (5) 1217-1221; DOI: https://doi.org/10.1124/mol.107.034538
Chika Koike
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Rick Moore
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Masahiko Negishi
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Abstract

The nuclear receptor constitutive active/androstane receptor (CAR) is sequestered in the cytoplasm of liver cells before its activation by therapeutic drugs and xenobiotics such as phenobarbital (PB) and 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in mouse liver, the regulatory mechanism of which remains poorly understood. Given the finding that epidermal growth factor repressed PB activation of CAR-mediated transcription (Mol Pharmacol65:172–180, 2004), here we investigated the regulatory role of hepatocyte growth factor (HGF)-mediated signal in sequestering CAR in the cytoplasm of mouse primary hepatocytes. HGF treatment effectively repressed the induction of endogenous CYP2b10 gene by PB and TCPOBOP in mouse primary hepatocytes. On the other hand, inhibition by 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) of an HGF downstream kinase mitogen-activated protein kinase kinase (MEK) induced the Cyp2b10 gene and up-regulated the CAR-regulated promoter activity in the absence of TCPOBOP. HGF treatment increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in the cytosol, thus decreasing the TCPOBOP-induced nuclear accumulation of CAR. In contrast, U0126 dephosphorylated ERK1/2 and increased nuclear CAR accumulation in the absence of TCPOBOP. These results are consistent with the conclusion that the HGF-dependent phosphorylation of ERK1/2 is the endogenous signal that sequesters CAR in the cytoplasm of mouse primary hepatocytes.

Footnotes

  • This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. C.K. is a Japan Society for the Promotion of Science Research Fellow in the Biomedical and Behavioral Research Program at National Institutes of Health.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.034538.

  • ABBREVIATIONS: CAR, constitutive active/androstane receptor; PB, phenobarbital; Hsp90, 90-kDa heat shock protein; CCRP, cytoplasmic CAR retention protein; EGF, epidermal growth factor; PBREM, phenobarbital-responsive enhancer module; MEK, mitogen-activated protein kinase kinase; U0124, 1,4-diamino-2,3-dicyano-1,4-bis(aminophenylthio)butadiene; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; ERK, extracellular signal-regulated kinase; TCPOBOP, 1, 4-bis[2-(3,5-dichloropyridyloxy)]benzene; kb, kilobase pair(s); RT-PCR, reverse transcription-polymerase chain reaction; HGF, hepatocytes growth factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; mCAR, mouse CAR; DMSO, dimethyl sulfoxide; KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine; AMPK, AMP kinase; KO, knockout; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one.

    • Received February 5, 2007.
    • Accepted February 21, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (5)
Molecular Pharmacology
Vol. 71, Issue 5
1 May 2007
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Extracellular Signal-Regulated Kinase Is an Endogenous Signal Retaining the Nuclear Constitutive Active/Androstane Receptor (CAR) in the Cytoplasm of Mouse Primary Hepatocytes

Chika Koike, Rick Moore and Masahiko Negishi
Molecular Pharmacology May 1, 2007, 71 (5) 1217-1221; DOI: https://doi.org/10.1124/mol.107.034538

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Extracellular Signal-Regulated Kinase Is an Endogenous Signal Retaining the Nuclear Constitutive Active/Androstane Receptor (CAR) in the Cytoplasm of Mouse Primary Hepatocytes

Chika Koike, Rick Moore and Masahiko Negishi
Molecular Pharmacology May 1, 2007, 71 (5) 1217-1221; DOI: https://doi.org/10.1124/mol.107.034538
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