title: Transcription coactivator PRIP, the peroxisome proliferator-activated receptor (PPAR)-interacting protein, is redundant for the function of nuclear receptors PParalpha and CAR, the constitutive androstane receptor, in mouse liver.
abstract: Disruption of the genes encoding for the transcription coactivators, peroxisome proliferator-activated receptor (PPAR)-interacting protein (PRIP/ASC-2/RAP250/TRBP/NRC) and PPAR-binding protein (PBP/TRAP220/DRIP205/MED1), results in embryonic lethality by affecting placental and multiorgan development. Targeted deletion of coactivator PBP gene in liver parenchymal cells (PBP(LIV-/-)) results in the near abrogation of the induction of PPARalpha and CAR (constitutive androstane receptor)-regulated genes in liver. Here, we show that targeted deletion of coactivator PRIP gene in liver (PRIP(LIV-/-)) does not affect the induction of PPARalpha-regulated pleiotropic responses, including hepatomegaly, hepatic peroxisome proliferation, and induction of mRNAs of genes involved in fatty acid oxidation system, indicating that PRIP is not essential for PPARalpha-mediated transcriptional activity. We also provide additional data to show that liver-specific deletion of PRIP gene does not interfere with the induction of genes regulated by nuclear receptor CAR. Furthermore, disruption of PRIP gene in liver did not alter zoxazolamine-induced paralysis, and acetaminophen-induced hepatotoxicity. Studies with adenovirally driven EGFP-CAR expression in liver demonstrated that, unlike PBP, the absence of PRIP does not prevent phenobarbital-mediated nuclear translocation/retention of the receptor CAR in liver in vivo and cultured hepatocytes in vitro. These results show that PRIP deficiency in liver does not interfere with the function of nuclear receptors PPARalpha and CAR. The dependence of PPARalpha- and CAR-regulated gene transcription on coactivator PBP but not on PRIP attests to the existence of coactivator selectivity in nuclear receptor function.
authors.affiliation: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Sarkar
authors.forename: Chao
authors.initials: C
authors.lastname: Qi
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Guo
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Ahmed
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Jia
authors.forename: Nobuteru
authors.initials: N
authors.lastname: Usuda
authors.forename: Navin
authors.initials: N
authors.lastname: Viswakarma
authors.forename: M Sambasiva
authors.initials: MS
authors.lastname: Rao
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D005786:Gene Expression Regulation; D018390:Gene Targeting; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009125:Muscle Relaxants, Central / Q000378:metabolism; D056918:Nuclear Receptor Coactivators; D009929:Organ Size; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015049:Zoxazolamine / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D000927:Anticonvulsants; D000090702:Constitutive Androstane Receptor; D047908:Intracellular Signaling Peptides and Proteins; D009125:Muscle Relaxants, Central; C405683:Ncoa6 protein, mouse; D056918:Nuclear Receptor Coactivators; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000082:Acetaminophen; D015049:Zoxazolamine; D010634:Phenobarbital