Beato M, Klug J
Institut für Molekularbiologie und Tumorforschung, IMT, Philipps-Universität, Marburg, Germany.
Hum Reprod Update. 2000 May-Jun;6(3):225-36. doi: 10.1093/humupd/6.3.225.
Steroid hormones (SHs) are lipophilic molecules derived from cholesterol and synthesized in the adrenal cortex (glucocorticoids, mineralocorticoids, and adrenal androgens), the testes (testicular androgens, oestrogen), and the ovary and placenta (oestrogens and progestagens or progestins). SHs reach their target cells via the blood, where they are bound to carrier proteins, and because of their lipophilic nature pass the cell membrane by simple diffusion. Within the target cells SHs bind to steroid hormone receptors (SHRs), the key mediators of SH action, which are complexed to chaperones, e.g. heat shock protein 90 (Hsp90), that help other proteins to fold and prevent aggregation. SHRs are intracellular transcription factors that can be activated, among other possibilities, by the specific and high affinity binding of ligand to exert positive or negative effects on the expression of target genes. Binding of agonistic or antagonistic ligands leads to different allosteric changes of SHRs making them competent to exert positive or negative effects on the expression of target genes by different mechanisms. (i) After dissociation of chaperones the liganded SHR-complexes can bind to chromatin organized DNA sequences in the vicinity of target genes, termed hormone response elements (HREs). The HRE-recruited hormone-receptor-complexes are then able to initiate chromatin remodelling and to relay activating or repressing signals to the target genes transcription machinery; (ii) through protein-protein interactions with other sequence-specific transcription factors, SHRs can also regulate the activity of many genes that are switched on, for instance, during stress or an inflammatory response; (iii) the SH response can also be integrated in the intracellular signalling network via cross-talk of SHRs with signal transduction pathways that transmit extracellular signals via membrane receptors and activation of protein kinase cascades to nuclear transcription factors that activate various target genes. By all these different mechanisms SHRs modulate numerous and specific responses in a large variety of cells, whereby their particular effect depends on the physiological, cellular and genetic context.
类固醇激素（SHs）是源自胆固醇的亲脂性分子，在肾上腺皮质（糖皮质激素、盐皮质激素以及肾上腺雄激素）、睾丸（睾丸雄激素、雌激素）、卵巢和胎盘（雌激素和孕激素或孕酮）中合成。SHs通过血液到达其靶细胞，在血液中它们与载体蛋白结合，并且由于其亲脂性通过简单扩散穿过细胞膜。在靶细胞内，SHs与类固醇激素受体（SHRs）结合，SHRs是SH作用的关键介质，它们与伴侣蛋白如热休克蛋白90（Hsp90）复合，Hsp90帮助其他蛋白质折叠并防止聚集。SHRs是细胞内转录因子，除其他可能性外，可通过配体的特异性和高亲和力结合而被激活，从而对靶基因的表达产生正向或负向影响。激动剂或拮抗剂配体的结合导致SHRs发生不同的变构变化，使其能够通过不同机制对靶基因的表达产生正向或负向影响。（i）伴侣蛋白解离后，与配体结合的SHR复合物可与靶基因附近的染色质组织DNA序列结合，这些序列称为激素反应元件（HREs）。然后，被HRE招募的激素 - 受体复合物能够启动染色质重塑，并将激活或抑制信号传递给靶基因转录机制；（ii）通过与其他序列特异性转录因子的蛋白质 - 蛋白质相互作用，SHRs还可以调节许多例如在应激或炎症反应期间开启的基因的活性；（iii）SH反应也可以通过SHRs与信号转导途径的相互作用整合到细胞内信号网络中，信号转导途径通过膜受体传递细胞外信号并激活蛋白激酶级联反应，进而激活各种靶基因的核转录因子。通过所有这些不同机制，SHRs调节多种细胞中的众多特异性反应，其特定作用取决于生理、细胞和遗传背景。
