Hyperfunctioning
adrenocortical adenomas produce excessive amounts of various
corticosteroids due to dysregulated expression of steroidogenic
enzymes. Since no genetic mutations in steroidogenic
enzyme genes have been identified as yet, the dysregulated expression at the transcription level may be crucial.
Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) and steroidogenic factor-1 (SF-1) play key roles in the transcriptional regulation of steroidogenic P450 genes. Transfection studies showed that SF-1 activated and COUP-TFs repressed the transcription of bovine
CYP17 gene promoter from the CRS2
element in a mutually exclusive manner in Y-1 cells. The results indicate that COUP-TFs negatively regulate the transcriptional activity of SF-1, a steroidogenic cell-specific activator of various steroidogenic P450 genes. Expression of both COUP-TFI and COUP-TFII was significantly decreased in the
cortisol-producing
adenomas, in which
CYP17 was drastically overexpressed, indicating that decreased expression of COUP-TFs play a key role in overexpression of
CYP17 in this type of
tumors. We then screened for COUP-TFI-interacting
proteins from a
cortisol-producing
adenoma cDNA library using a yeast two-hybrid system and identified a novel RING finger-containing
protein which can function as a coregulator for COUP-TFI. Notably, COUP-TFI activated rather than repressed several target genes including the human
CYP11B2 gene promoter, the results of which were opposite to those of the
CYP17 promoter. The bifunctional activities of COUP-TFI may be derived from the promoter context and our newly identified COUP-TFI coregulator.