Molecular mechanisms, physiological consequences and pharmacological implications of estrogen receptor action.
Molecular mechanisms, physiological consequences and pharmacological implications of estrogen receptor action.
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DOI：
10.2165/00129785-200404010-00003
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发表时间：
2004-01-01
期刊：
影响因子：
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通讯作者：
Gustafsson, Jan-Ake
中科院分区：
文献类型：
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作者：
Barkhem, Tomas;Nilsson, Stefan;Gustafsson, Jan-Ake
雌激素受体（ER），ER α和ER β，在介导雌激素的生物学效应中起核心作用。雌激素靶基因的转录速率由几个参数决定，包括配体的类型、雌激素受体亚型和同种型以及与受体结合辅因子蛋白的相互作用。ER通过与雌激素靶基因启动子中的特异性反应元件序列结合来调节基因表达。也已经描述了替代途径，其中ER通过蛋白质：蛋白质相互作用间接调节转录。在这种调控模式中，这已被追溯到激活蛋白（AP）-1-，环腺苷酸（cAMP）-，和Sp1-响应元件，ER似乎是通过异源转录因子拴在靶基因启动子。已经发现ER α和ER β对通过间接作用模式介导的转录具有相反的作用。此外，最近的研究表明，ER β可以抑制ER α对细胞增殖的刺激作用。雌激素是影响许多生理过程的关键调节激素。雌激素是女性青春期发育所必需的，影响女性生殖系统的生长、分化和功能。最近有人提出，雌激素在男性泌尿生殖道也有重要作用。此外，雌激素对其他组织也有深远的影响。例如，在骨骼中，雌激素通过抑制破骨细胞功能来防止骨吸收。许多报告表明，雌激素对心血管系统和中枢神经系统有有益作用;然而，这尚未在随机临床试验中得到证实。事实上，一项对健康绝经后妇女进行的大型随机试验显示，口服雌激素加炔雌醇增加了心血管疾病的发病率。此外，这项研究表明，接受口服雌激素/孕激素的人群患痴呆症和认知功能受损的风险增加。需要进行额外的临床试验，以确定哪种激素成分导致这些健康风险，或者这些影响是否是由于雌激素和雌激素的组合。
The estrogen receptors (ERs), ERalpha and ERbeta, play a central role in mediating the biological effects of estrogen. The transcription rate of estrogen target genes is determined by several parameters including the type of ligand, estrogen receptor subtype and isoform, as well as interactions with receptor-binding cofactor proteins. The ERs regulate gene expression by binding to specific response element sequences in the promoters of estrogen target genes. Alternative pathways have also been described in which the ERs modulate transcription indirectly, via protein : protein interactions. In this regulatory mode, which has been traced to activator protein (AP)-1-, cyclic adenosine monophosphate (cAMP)-, and Sp1-response elements, the ERs appear to be tethered to target gene promoters via heterologous transcription factors. It has been found that ERalpha and ERbeta have opposite effects on transcription mediated via the indirect mode of action. Moreover, recent studies suggest that ERbeta may inhibit the stimulatory effects of ERalpha on cellular proliferation. Estrogen is a key regulatory hormone that affects numerous physiological processes. Estrogen is required for female pubertal development and affects growth, differentiation and function of the female reproductive system. It has recently been suggested that estrogen also has an important role in the male urogenital tract. In addition, estrogens have profound effects in other tissues. For instance, in the skeleton estrogen prevents bone-resorption by inhibition of osteoclast function. Numerous reports have suggested that estrogen has a beneficial effect in the cardiovascular system and in the CNS; however, this has not been confirmed in randomized clinical trials. In fact, a large randomized trial on healthy postmenopausal women receiving oral estrogen plus progestin showed an increased incidence of cardiovascular disease. In addition, this study revealed an increased risk for dementia and impaired cognitive function in the group receiving oral estrogen/progestin. Additional clinical trials are required to determine which hormonal component causes these health risks or whether the effects were due to the combination of estrogen and progestin.