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[Nuclear receptors in the pathophysiology of endocrine tumors]
1Health Center, Department of Internal Medicine, School of Medicine, Keio University.
Abstract:
Nuclear orphan receptors COUP-TF and DAX-1 negatively regulate the transcriptional activity of SF-1, a steroidogenic cell-specific activator of various steroidogenic cytochrome P-450 genes. Expression of COUP-TF and DAX-1 are greatly decreased in cortisol-producing adrenocortical adenomas, while CYP17 is overexpressed. In contrast, DAX-1 expression is increased and SF-1 expression is decreased in deoxycorticosterone-producing adrenocortical adenomas, where CYP17 expression is low. These data suggest that DAX-1 and/or COUP-TF may repress CYP17 expression in adrenocortical tumors. In addition, SF-1 is expressed in the human pituitary gonadotroph and pituitary adenomas of gonadotrophic origin. SF-1 expression is associated with the in vitro secretion of LH in pituitary adenomas. Opposing effects of SF-1 and DAX-1 and/or COUP-TF may regulate the differential responses of various SF-1 target genes in different endocrine tumors.
Insights
Nuclear orphan receptors COUP-TF and DAX-1 regulate SF-1 activity, impacting steroidogenic gene expression. Their altered levels in adrenal tumors suggest a role in tumor development and differential gene regulation.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Context:
- Steroidogenic factor 1 (SF-1) is a key regulator of steroidogenic cytochrome P-450 genes.
- Nuclear orphan receptors COUP-TF and DAX-1 are known negative regulators of SF-1 transcriptional activity.
- Adrenocortical adenomas exhibit altered expression of these nuclear receptors and SF-1 target genes, such as CYP17.
Purpose:
- To investigate the roles of COUP-TF and DAX-1 in regulating SF-1 activity in the context of endocrine tumors.
- To correlate the expression levels of COUP-TF, DAX-1, and SF-1 with specific types of adrenocortical adenomas and their gene expression profiles.
- To explore the potential involvement of these nuclear receptors in the pathogenesis of pituitary adenomas.
Summary:
- Expression of COUP-TF and DAX-1 is decreased in cortisol-producing adenomas with high CYP17, while increased DAX-1 and decreased SF-1 are observed in deoxycorticosterone-producing adenomas with low CYP17.
- These findings suggest that DAX-1 and/or COUP-TF may repress CYP17 expression in adrenocortical tumors.
- SF-1 is also present in pituitary gonadotrophs and gonadotrophic adenomas, where its expression correlates with luteinizing hormone (LH) secretion, indicating a broader role in endocrine regulation.
Impact:
- Provides insights into the molecular mechanisms underlying different types of adrenocortical adenomas.
- Highlights the potential of DAX-1 and COUP-TF as therapeutic targets in endocrine tumorigenesis.
- Suggests that the interplay between SF-1, DAX-1, and COUP-TF is crucial for regulating SF-1 target genes in various endocrine tumors, including pituitary adenomas.