TY - JOUR
T1 - P38 MAP Kinase links CAR activation and inactivation in the nucleus via phosphorylation at threonine 38
AU - Hori, Takeshi
AU - Moore, Rick
AU - Negishi, Masahiko
N1 - Publisher Copyright:
© 2016 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2016
Y1 - 2016
N2 - 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. Herewe 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 p38MAPK exerted dual regulation by sequentially activating and inactivating CAR-mediated transcription through phosphorylation of threonine 38.
AB - 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. Herewe 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 p38MAPK exerted dual regulation by sequentially activating and inactivating CAR-mediated transcription through phosphorylation of threonine 38.
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U2 - 10.1124/dmd.116.070235
DO - 10.1124/dmd.116.070235
M3 - Article
C2 - 27074912
AN - SCOPUS:85011382703
VL - 44
SP - 871
EP - 876
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
SN - 0090-9556
IS - 6
ER -