Two-stage glucocorticoid induction of CYP3A23 through both the glucocorticoid and pregnane X receptors.
Glucocorticoid inducibility of the CYP3A23 gene is conferred by a multisite unit comprising binding sites for several members of the nuclear receptor superfamily of transcription factors, including the chicken ovalbumin upstream promoter-transcription factor COUP-TF, pregnane X receptor (PXR), and hepatocyte nuclear factor 4 (HNF-4). The presence of three binding sites, each of which interacts with more than one factor, contributes to the complexity of the CYP3A23 glucocorticoid-responsive region. Despite the glucocorticoid sensitivity of this gene, direct binding of ligand-activated glucocorticoid receptor (GR) to the CYP3A23 dexamethasone-responsive region (DexRE) is not required for induction. This study demonstrates that DexRE-2 is the key element within the CYP3A23 proximal promoter, conferring ligand sensitivity via its interaction with the PXR/RXRalpha heterodimer. The DexRE-1 and HNF-4 sites are not ligand-responsive, but are essential accessory elements required for full promoter inducibility. In addition to ligand-mediated activation of PXR, the overall induction response involves a GR-mediated stimulation of PXR and RXRalpha expression. Hence, the induction pathway can be divided into two stages. In stage one, maximal induction requires a GR-dependent increase in PXR and RXRalpha expression, and stage two is characterized by direct transcriptional activation of CYP3A23, which is dependent on ligand-activated PXR as well as accessory factors bound at the DexRE-1 and HNF-4 sites. Because multiple proteins bind at each element within the glucocorticoid-responsive region, factors not contributing to ligand responsiveness, such as chicken ovalbumin upstream promoter-transcription factor, may modulate the response through competitive interactions.
Huss
J M
JM
Department of Oncology and the Environmental Toxicology Program, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706, USA.
Kasper
C B
CB
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D020137:Base Pair Mismatch; D001483:Base Sequence; D002522:Chlorocebus aethiops; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D014407:Tumor Cells, Cultured
D005938:Glucocorticoids; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; C028697:dexamethasone receptor; D011285:Pregnenolone Carbonitrile; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A