COUP-TFI expression in human adrenocortical adenomas: Possible role in steroidogenesis

Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is an orphan nuclear receptor essential for neurogenesis, organogenesis, and cel l fate determination. CYP17 gene transcription has recently been shown to b e activated by SF-1 (steroidogenic factor-1) binding to a cyclic AMP-respon sive sequence within the promoter region of the gene, and inhibited by COUP -TF binding to the sequence. Thus, COUP-TF and SF-1 act as a transcriptiona l repressor and activator, respectively, of CYP17 gene expression. Transcri ptional repression by COUP-TFI is mediated by corepressors, N-CoR (nuclear receptor-corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone-receptor), whereas transcriptional activation by SF-1 is mediated by coactivator SRC-1 (steroid receptor coactivator-1). We therefore examine d the expression of COUP-TFI, SF-1, SRC-1, N-CoR, and SMRT in a variety of adrenocortical adenomas and compared the results with CYP17 mRNA levels. We found significantly high COUP-TFI mRNA expression in nonfunctional adenoma s (n=8: 220+/-16%; normal 96+/-4%), a deoxycorticosterone-producing adenoma (n=1: 200%), and a pre-clinical Cushing's adenoma (n=1: 280%), intermediat e COUP-TFI expression in cortisol-producing adenomas (n=8: 63+/-5%), and lo w COUP-TFI expression in aldosterone-producing adenomas (n=8: 49+/-4%). In contrast to COUP-TFI, SF-1 mRNA expression did not vary significantly among adrenals. We did not detect the expected negative correlation between COUP -TFI and CYP17 mRNA levels in adrenocortical adenomas. High COUP-TFI expres sion was associated with a nonfunctioning phenotype. Interestingly, the pat tern of COUP-TFI expression was similar to the profile of N-CoR expression, but not of SMRT expression. These results indicate that COUP-TFI and N-CoR may play a role in steroidogenesis by human adrenocortical adenomas.