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Research ArticleArticle

p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38

Takeshi Hori, Rick Moore and Masahiko Negishi
Drug Metabolism and Disposition June 2016, 44 (6) 871-876; DOI: https://doi.org/10.1124/dmd.116.070235
Takeshi Hori
Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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Rick Moore
Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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Masahiko Negishi
Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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This article has a correction. Please see:

  • Correction to “p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38 s” - April 01, 2017

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Abstract

Nuclear receptor constitutive androstane receptor (CAR, NR1I3), which regulates hepatic drug and energy metabolisms as well as cell growth and death, is sequestered in the cytoplasm as its inactive form phosphorylated at threonine 38. CAR activators elicit dephosphorylation, and nonphosphorylated CAR translocates into the nucleus to activate its target genes. CAR was previously found to require p38 mitogen-activated protein kinase (MAPK) to transactivate the cytochrome P450 2B (CYP2B) genes. Here we have demonstrated that p38 MAPK forms a complex with CAR, enables it to bind to the response sequence, phenobarbital-responsive enhancer module (PBREM), within the CYP2B promoter, and thus recruits RNA polymerase II to activate transcription. Subsequently, p38 MAPK elicited rephosphorylation of threonine 38 to inactivate CAR and exclude it from the nucleus. Thus, nuclear p38 MAPK exerted dual regulation by sequentially activating and inactivating CAR-mediated transcription through phosphorylation of threonine 38.

Footnotes

    • Received February 25, 2016.
    • Accepted April 1, 2016.
  • This work was supported by the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences [Grant Z01ES71005-01].

  • dx.doi.org/10.1124/dmd.116.070235.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 44 (6)
Drug Metabolism and Disposition
Vol. 44, Issue 6
1 Jun 2016
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Research ArticleArticle

p38 MAPK Links CAR Activation and Inactivation

Takeshi Hori, Rick Moore and Masahiko Negishi
Drug Metabolism and Disposition June 1, 2016, 44 (6) 871-876; DOI: https://doi.org/10.1124/dmd.116.070235

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Research ArticleArticle

p38 MAPK Links CAR Activation and Inactivation

Takeshi Hori, Rick Moore and Masahiko Negishi
Drug Metabolism and Disposition June 1, 2016, 44 (6) 871-876; DOI: https://doi.org/10.1124/dmd.116.070235
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