人類子宮內膜異位症組織異常地表現固醇類賀爾蒙生成急性調控蛋白（StAR）對於固醇類的生成，以致於子宮內膜異位症的成因扮演著很重要的角色。前人的研究指出前列腺素E2（PGE2）可以促進固醇類賀爾蒙生成急性調控蛋白的表現，而本實驗的目的即是要探討前列腺素E2的訊息傳導如何在轉錄的層次上調節固醇類賀爾蒙生成急性調控蛋白的表現。人類子宮內膜異位症基質細胞表現有E型前列腺素接受器第二、三、四亞型（EP2, EP3 and EP4），而前列腺素E2主要透過EP2促進固醇類賀爾蒙生成急性調控蛋白的表現。前列腺素E2經由EP2促進固醇類賀爾蒙生成急性調控蛋白的表現是透過蛋白質激脢A（PKA），而非透過細胞分裂原活化激脢（MAPK）的傳遞路徑。前列腺素E2可以引發單磷酸環腺?反應元件結合蛋白（CREB）的磷酸化，進而募集CREB結合蛋白（CBP）。而透過免疫沈降的實驗證明，前列腺素E2所引發的CREB、CBP與組蛋白（histone）複合體也是依靠蛋白質激脢A的作用。更進一步使用染色質體免疫沈降實驗方法來分析，結果顯示在處理前列腺素E2 60分鐘之後，結合在固醇類賀爾蒙生成急性調控蛋白近端促進子上的組蛋白乙醯化程度增加了，並伴隨著初生核醣核酸（nascent RNA）的產生。而用組蛋白去乙醯脢的抑制劑（HDAC inhibitor, tricostatin A）前處理細胞則可以增強前列腺素E2所促進的固醇類賀爾蒙生成急性調控蛋白初生核醣核酸產量。在另外的實驗中，以EP3同功物（EP3 agonist, sulprostone）共處理可以減弱前列腺素E2所促進的固醇類賀爾蒙生成急性調控蛋白生成；阻斷磷酸脂切割脢C（PLC）與鈣離子訊息傳遞鏈可以增強前列腺素E2所促進的固醇類賀爾蒙生成急性調控蛋白初生核醣核酸產量。此增強作用是透過增加CREB與CBP的交互作用，而非影響CREB的磷酸化。因此，前列腺素E2可以透過EP3及其下游的鈣離子訊息傳遞鏈干擾CREB與CBP的交互作用，進而減弱EP2所傳導促進的固醇類賀爾蒙生成急性調控蛋白表現。總而言之，本論文研究結果可推論出在子宮內膜異位症組織上前列腺素E2引發固醇類賀爾蒙生成急性調控蛋白表現的機制，那就是前列腺素E2透過EP2活化其下游的蛋白質激脢A，來增加CREB的磷酸化、CBP的募集和固醇類賀爾蒙生成急性調控蛋白促進子上組蛋白的乙醯化，進而增加固醇類賀爾蒙生成急性調控蛋白的轉錄與轉譯。

　　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.

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