Published online before print June 26, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2008.080199v1 173/2/433    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Hsu, C.-C. Articles by Tsai, S.-J. PubMed PubMed Citation Articles by Hsu, C.-C. Articles by Tsai, S.-J.

(American Journal of Pathology. 2008;173:433-441.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080199

Cyclic Adenosine 3',5'-Monophosphate Response Element-Binding Protein and CCAAT/Enhancer-Binding Protein Mediate Prostaglandin E₂-Induced Steroidogenic Acute Regulatory Protein Expression in Endometriotic Stromal Cells

Chih-Chao Hsu^*, Chun-Wun Lu, Bu-Miin Huang, Meng-Hsing Wu and Shaw-Jenq Tsai^*

From the Department of Physiology,^* the Institute of Basic Medical Sciences, and the Departments of Cell Biology and Anatomy and Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

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/EBP, C/EBPβ, and CREB. Forced expression of either C/EBP 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.