Molecular and cellular mechanisms of PGE2-induced StAR expression in human endometriotic stromal cells

• Main Authors: Kuei-Yang Hsiao, 蕭貴陽
• Other Authors: Shaw-Jenq Tsai
• Format: Others
• Language: en_US
• Published: 2002
• Online Access: http://ndltd.ncl.edu.tw/handle/55559176319381357801

碩士 === 國立成功大學 === 生理學研究所 === 91 === 　　Aberrant expression of steroidogenic acute regulatory protein (StAR) in human endometriotic stromal cells plays important roles in the biosynthesis of steroids and etiology of endometriosis. Previous study indicated that prostaglandin E2 (PGE2) has a potent effect on induction of StAR expression. The objective of the present study was to characterize the role of PGE2 signaling in the transcriptional regulation of StAR gene expression. Three of four E-type prostanoid receptors (EPs), EP2, EP3 and EP4, were expressed in endometriotic stromal cells and PGE2-induced StAR expression was mediated through EP2 but not EP3 or EP4. PGE2-induced EP2-mediated StAR expression was through PKA-dependent pathway but is independent of mitogen-activated protein kinase signaling. Treatment of PGE2 induced phosphorylation of cyclic AMP responding element binding protein (CREB) and recruitment of CREB-binding protein (CBP). The formation of CREB, CBP and histone complexes was induced by PGE2 treatment and this association was also a PKA dependent event. Results from chromatin immunoprecipitation and realtime PCR assays demonstrated that histone H3 bound to proximal region of StAR promoter was acetylated after 60 min of PGE2 treatment and this was followed by increase in nascent StAR RNA transcription. Treatment with the histone deacetylase inhibitor, tricostatin A, enhanced PGE2-induced nascent StAR RNA production. Pretreatment of EP3 agonist attenuated PGE2-induced StAR expression. Blockage of phospholipase C and calcium signalings at downstream of EP3 enhanced StAR transcription, and this effect may be mediated through increased CREB-CBP interaction but not CREB phosphorylation. Thus, PGE2 exerts a negative regulation on StAR transcription through EP3-calcium signaling to interfere in CREB-CBP interaction. In conclusion, binding of PGE2 to EP2 in human endometriotic stromal cells induces PKA-dependent CREB phosphorylation, CBP-recruitment, and StAR promoter-bound histone H3 acetylation and thus leads to increase in StAR transcription and translation.