Regulation of differential COUP-TF-coregulator interactions in adrenal cortical steroidogenesis.

Abstract

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.

• Authors: Hirotaka Shibata, Isao Kurihara, Sakiko Kobayashi, Kenichi Yokota, Noriko Suda, Ikuo Saito, Takao Saruta
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 85 Issue 2-5 Pg. 449-56 (Jun 2003) ISSN: 0960-0760 [Print] England
• PMID: 12943735 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Adrenal Cortex Hormones
• COUP Transcription Factor II
• COUP Transcription Factors
• DNA-Binding Proteins
• NR2F2 protein, human
• NR5A1 protein, human
• Receptors, Steroid
• Steroidogenic Factor 1
• Transcription Factors
• Steroid 17-alpha-Hydroxylase

Topics

• Adrenal Cortex (physiology)
• Adrenal Cortex Hormones (biosynthesis)
• Animals
• COUP Transcription Factor II
• COUP Transcription Factors
• Cattle
• DNA-Binding Proteins (genetics, physiology)
• Gene Expression Regulation
• Humans
• Receptors, Steroid
• Steroid 17-alpha-Hydroxylase (genetics)
• Steroidogenic Factor 1
• Transcription Factors (genetics, physiology)