Article

Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene

Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Molecular and Cellular Biology (Impact Factor: 5.04). 10/1999; 19(9):6318-22.
Source: PubMed

ABSTRACT The constitutively active receptor (CAR) transactivates a distal enhancer called the phenobarbital (PB)-responsive enhancer module (PBREM) found in PB-inducible CYP2B genes. CAR dramatically increases its binding to PBREM in livers of PB-treated mice. We have investigated the cellular mechanism of PB-induced increase of CAR binding. Western blot analyses of mouse livers revealed an extensive nuclear accumulation of CAR following PB treatment. Nuclear contents of CAR perfectly correlate with an increase of CAR binding to PBREM. PB-elicited nuclear accumulation of CAR appears to be a general step regulating the induction of CYP2B genes, since treatments with other PB-type inducers result in the same nuclear accumulation of CAR. Both immunoprecipitation and immunohistochemistry studies show cytoplasmic localization of CAR in the livers of nontreated mice, indicating that CAR translocates into nuclei following PB treatment. Nuclear translocation of CAR also occurs in mouse primary hepatocytes but not in hepatocytes treated with the protein phosphatase inhibitor okadaic acid. Thus, the CAR-mediated transactivation of PBREM in vivo becomes PB responsive through an okadaic acid-sensitive nuclear translocation process.

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    • "Promiscuous NRs bind to a wide range of different molecules and, depending on the molecule, activate the transcription of a wide range of proteins. Some of these promiscuous NRs are involved in inducing phase I-III responses following exposure to toxicants (Kliewer et al., 1998; Kawamoto et al., 1999; Wei et al., 2000; King-Jones et al., 2006; Karimullina et al., 2012). It has been hypothesized that specificity/promiscuity comes into play when examining the evolution of nuclear receptors due to natural selection. "
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    Gene 09/2014; 552(1). DOI:10.1016/j.gene.2014.09.024 · 2.08 Impact Factor
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    • "phenobarbital (PB)-like inducers via interactions with DR4 motifs (Kawamoto et al. 1999). It therefore acts as a xenobiotic-sensing nuclear receptor. "
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