title: p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38.
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.
authors.affiliation: Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hori
authors.affiliation: Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
authors.forename: Rick
authors.initials: R
authors.lastname: Moore
authors.affiliation: Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina negishi@niehs.nih.gov.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Negishi
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D010634:Phenobarbital / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000090702:Constitutive Androstane Receptor; C000716328:Nr1i3 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D013912:Threonine; D001189:Aryl Hydrocarbon Hydroxylases; D048051:p38 Mitogen-Activated Protein Kinases; D010634:Phenobarbital