Liver receptor homolog-1 regulates the expression of steroidogenic acute regulatory protein in human granulosa cells.

Abstract

Steroidogenic acute regulatory protein (StAR) plays a critical role in the initial step of steroid hormone synthesis. In the present study, we investigated the role of liver receptor homolog-1 (LRH-1) and dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X chromosome, gene 1 (DAX-1) in the regulation of StAR gene expression in human granulosa cell tumor cells. We also examined the effect of protein kinase A (PKA) signaling pathway on the expression of StAR in the presence of LRH-1 and DAX-1. Cell transfection, mutation analysis, and EMSA were performed. LRH-1 significantly induced StAR promoter activity in a concentration-dependent manner. This induction was further augmented in the presence of PKA agonist. Using deletion analysis, we demonstrated LRH-1 binding site at -105/-95. Mutation of this site resulted in a significant decrease in the StAR promoter activity. Using EMSA, the ability of this cis-element to bind LRH-1 was confirmed. DAX-1 inhibited LRH-1-stimulated StAR promoter activity in a concentration-dependent manner. This inhibition was also maintained in the presence of PKA stimulation. Our results demonstrated that LRH-1 plays a critical role in the induction of StAR gene expression. We hypothesize that LRH-1 could be the major transcription factor responsible for the rapid and significant increase in ovarian StAR gene expression after ovulation.

• Authors: Joung Woul Kim, Noel Peng, William E Rainey, Bruce R Carr, George R Attia
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 89 Issue 6 Pg. 3042-7 (Jun 2004) ISSN: 0021-972X [Print] United States
• PMID: 15181096 (Publication Type: Journal Article)

Chemical References

• DAX-1 Orphan Nuclear Receptor
• DNA-Binding Proteins
• NR0B1 protein, human
• Nr0b1 protein, mouse
• Nr5a2 protein, mouse
• Phosphoproteins
• Receptors, Cytoplasmic and Nuclear
• Receptors, Retinoic Acid
• Repressor Proteins
• steroidogenic acute regulatory protein
• Cyclic AMP-Dependent Protein Kinases

Topics

• Cell Line, Tumor
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• DAX-1 Orphan Nuclear Receptor
• DNA-Binding Proteins (metabolism)
• Electrophoretic Mobility Shift Assay
• Female
• Gene Expression
• Granulosa Cell Tumor
• Humans
• Ovarian Neoplasms
• Ovary (physiology)
• Ovulation (physiology)
• Phosphoproteins (genetics)
• Promoter Regions, Genetic (physiology)
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Receptors, Retinoic Acid (metabolism)
• Repressor Proteins (metabolism)
• Signal Transduction (physiology)