Aberrant expression of the steroidogenic acute regulatory (StAR) protein in human endometriotic stromal cells plays an important role in the development of endometriosis. Prostaglandin E2 (PGE2) is a potent inducer of StAR expression in these cells; however, the mechanisms responsible for the transcriptional regulation of StAR remain to be elucidated. Herein we report that PGE2-induced StAR expression is independent of the transcriptional suppressor DAX-1 but is regulated by the transcriptional activator cyclic adenosine 3′,5′-monophosphate (cAMP) response element-binding protein (CREB). A promoter activity assay revealed that the cis-element needed for the binding of the CCAAT/enhancer-binding protein (C/EBP) was critical for PGE2-induced StAR expression. Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPα, C/EBPβ, and CREB. Forced expression of either C/EBPα or C/EBPβ alone was sufficient to up-regulate StAR promoter activity whereas PGE2 was needed to induce StAR promoter activity in CREB-overexpressed cells. Results from a chromatin immunoprecipitation assay demonstrated that the binding of C/EBPβ to the StAR promoter was increased whereas CREB binding was unchanged after PGE2 treatment. Taken together, PGE2-induced StAR promoter activity appears to be regulated by CREB and C/EBPβ in a cooperative manner in ectopic human endometriotic stromal cells, providing a molecular framework for the etiology of endometriosis.
All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine