title: Cross-talk between constitutive androstane receptor and hypoxia-inducible factor in the regulation of gene expression.
abstract: Hypoxia inducible factor (HIF) and 5'-AMP-activated protein kinase are often activated under similar physiological conditions. Constitutive androstane receptor (CAR) translocates into the nucleus in accordance with 5'-AMP-activated protein kinase and thus confers transactivation. The aim of the present study was to investigate a possible link between CAR and HIFα. Phenobarbital (PB), a typical CAR activator, increased the gene expression of HIF-target genes in the livers of mice, including erythropoietin, heme oxygenase-1 and vascular endothelial growth factor-a. PB induced an accumulation of nuclear HIF-1α and an increase in the HIF-responsive element-mediated transactivation in HepG2 cells. Cobalt chloride, a typical HIF activator, induced the gene expression of CAR-target genes, including cyp2b9 and cyp2b10, an accumulation of nuclear CAR and an increase in the PB-responsive enhancer module-mediated transactivation in the mouse liver. Immunoprecipitation-immunoblot and chromatin immunoprecipitation analyses suggest that CAR binds to the PB-responsive enhancer module with HIF-1α in the liver of untreated mice and that the complex dissociates upon PB treatment. Taken together these results suggest that CAR and HIF-α interact and reciprocally modulate the functions of each other.
authors.affiliation: Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, Tokyo, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Shizu
authors.forename: Sawako
authors.initials: S
authors.lastname: Shindo
authors.forename: Takemi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Satoshi
authors.initials: S
authors.lastname: Numazawa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D003035:Cobalt / Q000494:pharmacology; D000090702:Constitutive Androstane Receptor; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects* / Q000235:genetics; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010634:Phenobarbital / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics
chemical_list: D000090702:Constitutive Androstane Receptor; D051793:Hypoxia-Inducible Factor 1; D018160:Receptors, Cytoplasmic and Nuclear; D003035:Cobalt; C018021:cobaltous chloride; D010634:Phenobarbital