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First published on February 21, 2007; DOI: 10.1124/mol.107.034538

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Received for publication February 6, 2007.
Revised February 21, 2007.
Accepted for publication February 21, 2007.

MEK-ERK is an endogenous signal retaining the nuclear receptor CAR in the cytoplasm of mouse primary hepatocytes

Chika Koike 1, Rick Moore 1, Masahiko Negishi 1*

1 NIEHS, NIH

* Address correspondence to: E-mail: negishi{at}niehs.nih.gov

Abstract

The nuclear receptor CAR is sequestered in the cytoplasm of liver cells before its activation by therapeutic drugs and xenobiotics such as phenobabrital (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 in rat primary hepatocytes (Bauer et. al., Mol. Pharmacol., 65, 172-180, 2004), here we investigated the regulatory role of hepatocytes 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 U0126 of a HGF-down stream kinase MEK induced the Cyp2b10 gene and up-regulated the CAR-regulated promoter activity in the absence of TCPOBOP. HGF treatment increased phosphorylation of ERK1/2 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 sequestering CAR in the cytoplasm of mouse primary hepatocytes.


Key words: NGF/EGF, MAP Kinase, Cytochrome P450, Regulation - xenobiotic


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