Cyp11a1 啟動子上的SF-1調控序列之生理及調控功能

CYP11A1是調控類固醇荷爾蒙生合成過程中的重要酵素。SF-1則為調控Cyp11a1基因表現的主要轉錄因子。為探討Cyp11a1之基因調控以及其生理功能，本論文以細胞培養的技術和SF1RE突變的基因轉殖小鼠進行深入的探討，研究證實Cyp11a1 啟動子近端之SF1RE具有細胞特異的轉錄調節功能。觀察SF1RE突變的Cyp11a1L/L小鼠，其腎上腺和睪丸CYP11A1的表現大幅降低，但卻不影響CYP11A1在卵巢的表現情形。儘管CYP11A1的表現在Cyp11a1L/L小鼠減少到正常的量的15%，然而在一般狀態之下，此小鼠的壽命、生殖能力、荷爾蒙濃度、以及行為表現卻都和正常小鼠相似。另一方面，減少CYP11A1的表現使得小鼠糖皮質激素的晝夜節律減緩，突變小鼠也無法分泌足夠的糖皮質激素應付壓力反應，致無法抑制發炎反應所誘導出的大量細胞激素，而增加小鼠的死亡率。此外，Cyp11a1L/L小鼠在饑餓狀態之下因缺乏足夠的糖皮質激素而無法維持其體內的能量平衡。本研究發現CYP11A1在正常小鼠的表現量遠大於其基本需求量，以特別應付壓力狀態。所以Cyp11a1 啟動子近端之SF1RE突變減低CYP11A1的表現，使得小鼠的腎上腺無法分泌足夠量的糖皮質激素應付壓力反應，繼而造成小鼠之異常壓力反應表現。

關鍵字

類固醇荷爾蒙生合成；基因調控；生理功能

並列摘要

CYP11A1 is a key enzyme in steroid hormone synthesis which is regulated by steroidogenic factor-1 (SF-1). In order to investigate the regulation and functions of Cyp11a1, I used the cell culture system and mice which were mutated on the SF-1 response element (SF1RE) of Cyp11a1 promoter for further studying. In this study, I demonstrated the mutated proximal SF1RE on Cyp11a1 promoter regulated its transcriptional activity cell type specifically. In Cyp11a1L/L mice, this mutation results in the decrease of CYP11A1 expression in the adrenal and testis, but the expression in the ovary was normal. Even though CYP11A1 expression level is reduced to 15% of the normal amount, the life span, fertility, steroid levels, and behavior of Cyp11a1L/L mice were similar as that of wildtype mice at the resting state. The reduction of CYP11A1 attenuated the circadian rhythm of corticosterone levels. These mice also failed to secrete more glucocorticoid in response to stress, leading to inability to inhibit the production of stress-induced inflammatory cytokines and increased mortality. In addition, mutant mice also showed defects in maintaining energy homeostasis when fasting. Thus, CYP11A1 appears in normal mice to be expressed above the minimal required level, providing a large reserve capacity for use in response to stress. Mutation of the SF1RE of Cyp11a1 results in reduced stress response due to decreased CYP11A1 expression and insufficient stress-induced glucocorticoids secretion.

並列關鍵字

Cyp11a1 ； SF-1 ； steroidogenesis ； gene regulation ； physiological function

參考文獻

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Cyp11a1 啟動子上的SF-1調控序列之生理及調控功能

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