Cross-talk between constitutive androstane receptor and hypoxia-inducible factor in the regulation of gene expression.
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.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-N
androstane 5'-AMP 5'-AMP Phenobarbital Cobalt chloride androstane Hypoxia inducible factor CAR PB-responsive enhancer module HIF-1α CAR HIF-α Constitutive androstane receptor CAR 5'-AMP-activated protein kinase HIF CAR 5'-AMP-activated protein kinase HIFα CAR HIF erythropoietin heme oxygenase-1 vascular endothelial growth factor-a HIF-1α HIF-responsive element HIF CAR cyp2b9 cyp2b10 CAR PB-responsive enhancer module constitutive androstane receptor hypoxia-inducible factor