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类固醇生成因子1对大鼠促卵泡激素受体启动子的激活被蛋白激酶A阻断,且需要上游刺激因子与近端E盒元件结合。

Activation of the rat follicle-stimulating hormone receptor promoter by steroidogenic factor 1 is blocked by protein kinase a and requires upstream stimulatory factor binding to a proximal E box element.

作者信息

Heckert L L

机构信息

Department of Molecular and Integrative Physiology The University of Kansas Medical Center Kansas City, Kansas 66160, USA.

出版信息

Mol Endocrinol. 2001 May;15(5):704-15. doi: 10.1210/mend.15.5.0632.

Abstract

The receptor for the pituitary glycoprotein hormone FSH (FSHR) and the nuclear hormone receptor steroidogenic factor 1 (SF-1) play important roles in control of the hypothalamic-pituitary- gonadal axis. FSHR is essential for integrating the pituitary FSH signal to gonadal response, while SF-1 is an important transcriptional regulator of many genes that function within this axis and is essential for the development of gonads and adrenal glands. Given the critical role of SF-1 in regulation of the gonads and the coexpression of FSHR and SF-1 in Sertoli and granulosa cells, we examined the ability of SF-1 to regulate transcription of the FSHR gene. We found that SF-1 stimulated rat FSHR promoter activity in a dose-dependent and promoter-specific manner. Examination of various promoter deletion mutants indicated that SF-1 acts through the proximal promoter region and upstream promoter sequences. An E box element within the proximal promoter is essential for activation of the FSHR promoter by SF-1. This element binds the transcriptional regulators USF1 and USF2 (upstream stimulatory factors 1 and 2) but not SF-1, as shown by electrophoretic mobility shift assays. In addition, functional studies identified a requirement for the USF proteins in SF-1 activation of FSHR and mapped an important regulatory domain within exons 4 and 5 of USF2. Cotransfection studies revealed that activation of protein kinase A leads to inhibition of SF-1-stimulated transcription of FSHR, while it synergized with SF-1 to activate the equine LH beta-promoter (ebeta). Thus, stimulation of the cAMP pathway differentially regulates SF-1 activation of the FSHR and ebeta-promoters.

摘要

垂体糖蛋白激素FSH的受体(FSHR)和核激素受体类固醇生成因子1(SF-1)在控制下丘脑-垂体-性腺轴中发挥重要作用。FSHR对于整合垂体FSH信号至性腺反应至关重要,而SF-1是该轴内许多发挥功能的基因的重要转录调节因子,对于性腺和肾上腺的发育必不可少。鉴于SF-1在性腺调节中的关键作用以及FSHR和SF-1在支持细胞和颗粒细胞中的共表达,我们研究了SF-1调节FSHR基因转录的能力。我们发现SF-1以剂量依赖性和启动子特异性方式刺激大鼠FSHR启动子活性。对各种启动子缺失突变体的研究表明,SF-1通过近端启动子区域和上游启动子序列发挥作用。近端启动子内的一个E盒元件对于SF-1激活FSHR启动子至关重要。如电泳迁移率变动分析所示,该元件结合转录调节因子USF1和USF2(上游刺激因子1和2),但不结合SF-1。此外,功能研究确定了USF蛋白在SF-1激活FSHR中的必要性,并在USF2的外显子4和5内定位了一个重要的调节域。共转染研究表明,蛋白激酶A的激活导致SF-1刺激的FSHR转录受到抑制,而它与SF-1协同激活马促黄体素β启动子(ebeta)。因此,cAMP途径的刺激以不同方式调节SF-1对FSHR和ebeta启动子的激活。

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