Constitutive androstane receptor-vitamin D receptor crosstalk: consequence on CYP24 gene expression.
We previously reported that the pregnane X receptor (PXR) interferes with vitamin D receptor (VDR) target genes, notably CYP24, by targeting the same responsive elements. Since PXR and constitutive androstane receptor (CAR) share responsive elements in the promoter of their target genes, we wondered whether CAR also interferes with CYP24 expression. The current study shows that: (i) CAR-RXR heterodimer binds to and transactivates the proximal promoter of CYP24 (-1200/+22) and both VDRE-1 and VDRE-2 which control its expression in response to 1,25-dihydroxyvitamin D(3), (ii) androstanol an inverse agonist of hCAR inhibits transactivation of VDREs by hCAR, (iii) mutations of either VDRE-1 or -2 half sites inhibit hCAR-mediated transactivation, and (iv) in primary human hepatocytes (n =11) CITCO, a specific hCAR agonist, is an inducer of CYP24 as well as of CYP2B6 and CYP3A4 mRNAs. In conclusion, CAR/PXR and VDR bind to and transactivate the same response elements in CYP24 promoter.
Moreau
Amélie
A
Inserm, Université Montpellier1, UMR-632, Montpellier F-34293, France.
Maurel
Patrick
P
Vilarem
Marie-José
MJ
Pascussi
Jean-Marc
JM
D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D015870:Gene Expression / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D018167:Receptors, Calcitriol / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013250:Steroid Hydroxylases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
D000090702:Constitutive Androstane Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase