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Vol. 58, Issue 1, 48-57, July 2000
Department of Oncology and the Environmental Toxicology Program,
McArdle Laboratory for Cancer Research, University of Wisconsin,
Madison, Wisconsin
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/RXR
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 RXR expression. Hence, the induction pathway can be divided into
two stages. In stage one, maximal induction requires a GR-dependent
increase in PXR and RXR 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.
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