PT  - JOURNAL ARTICLE
AU  - Janice M. Huss
AU  - Charles B. Kasper
TI  - Two-Stage Glucocorticoid Induction of <em>CYP3A23</em>through Both the Glucocorticoid and Pregnane X Receptors
AID  - 10.1124/mol.58.1.48
DP  - 2000 Jul 01
TA  - Molecular Pharmacology
PG  - 48--57
VI  - 58
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/58/1/48.short
4100  - http://molpharm.aspetjournals.org/content/58/1/48.full
SO  - Mol Pharmacol2000 Jul 01; 58
AB  - 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 theCYP3A23 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/RXRα 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 RXRα expression. Hence, the induction pathway can be divided into two stages. In stage one, maximal induction requires a GR-dependent increase in PXR and RXRα 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.