Activation of the glucocorticoid-receptor complex.
Activation of the glucocorticoid-receptor complex.
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糖皮质激素受体复合物的激活。
DOI：
10.1152/physrev.1982.62.4.1131
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发表时间：
1982
影响因子：
33.6
通讯作者：
Litwack,G
中科院分区：
文献类型：
--
作者：
Schmidt,TJ;Litwack,G
在许多脊椎动物中，糖皮质激素影响许多生理参数并在多种组织中引起深刻的细胞内生化改变。大量实验数据支持这样的概念：与其他类固醇激素一样，糖皮质激素的大部分作用是通过细胞内受体蛋白介导的，这些受体蛋白最初位于靶细胞的细胞质中，但最终必须转移到细胞核。尽管所分析的大多数组织和细胞都含有这些特定受体（综述见 143），但一种组织类型对糖皮质激素的表型反应有所不同。这些反应差异很大，包括分解代谢效应，例如淋巴细胞中的细胞裂解和死亡 (16, 44)，以及合成代谢效应，例如诱导有限数量的酶或抑制肝癌细胞中有限数量的功能 (83)。由于这种变异，受体占据与表型反应的程度明显相关。然而，尽管糖皮质激素与细胞内受体结合有明显的先决条件，但其对特定靶细胞发挥作用的精确机制尚不完全清楚。一旦糖皮质激素-受体复合物在细胞质中形成，它被认为会经历两步过程以与细胞核结合并最终影响基因表达。第一步，激活，取决于温度，也是本次审查的主题。据信该步骤涉及类固醇受体复合物的改变，导致分子表面带正电的区域暴露。请注意，一些研究人员使用术语“激活”来描述受体从非结合形式转变为糖皮质激素结合形式的过程，并使用术语“转化”来描述这种温度依赖性变化（103、181、182、229）。第二步不依赖于温度，称为易位，涉及先前激活（转化）的复合物移动到细胞核中，以及随后与染色质内的受体位点结合。这种核相互作用的最终结果是信使 RNA (mRNA) 合成的启动以及 mRNA 最终翻译成特定蛋白质，其活性构成表型反应。显然，激活和易位步骤之间的区别至关重要，并且了解这些过程背后的机制对于我们理解激素信息如何在靶细胞内传递至关重要。已经发表了许多综合性论文，综述了糖皮质激素的生理学和药理学的各个方面以及受体在介导广泛靶组织中的特异性反应中的作用（31、59、91、143、167、193、218）。在本综述中，我们试图避免重复这些信息，并将我们的注意力集中在糖皮质激素受体激活的各个生化和生理方面。我们尝试整合众多实验室发布的信息
In many vertebrate species glucocorticoids influence a number of physiological parameters and elicit profound intracellular biochemical alterations in a variety of tissues. A large volume of experimental data supports the concept that, as with other steroid hormones, most of these effects of glucocorticoids are mediated through intracellular receptor proteins that are initially located in the cytoplasm of target cells but that must ultimately be translocated to the nucleus. Although most of the tissues and cells analyzed contain these specific receptors (for review see 143), the phenotypic response to glucocorticoids differs from one tissue type to another.. These responses vary widely and include catabolic effects, such as cell lysis and death in lymphoid cells (16, 44), as well as anabolic effects, such as induction of a limited number of enzymes or suppression of a limited number of functions in hepatoma cells (83).Even with this variation, receptor occupancy clearly correlates with the extent of the phenotypic response. Despite this obvious prerequisite for binding to intracellular receptors, however, the precise mechanism by which glucocorticoids exert their effects on a particular target cell is not completely understood. Once the glucocorticoid-receptor complex is formed in the cytoplasm, it is thought to undergo a two-step process in order to bind to nuclei and ultimately affect gene expression. The first step, activation, is temperature dependent and is the subject of this review. This step is believed to involve an alteration in the steroid-receptor complex, resulting in the exposure of positively charged regions on the surface of the molecule. Note that some investigators use the term activation to describe the process whereby the receptor is converted from a nonbinding to a glucocorticoid-binding form and the term transformation to describe this temperature-dependent change (103, 181, 182, 229). The second step, which is not temperature dependent, is termed translocation and involyes the movement of the previously activated (transformed) complexes into the nucleus and their subsequent binding to acceptor sites within the chromatin. The net results of this nuclear interaction are initiation of messenger RNA (mRNA) synthesis and ultimate translation of mRNA into specific proteins whose activities constitute the phenotypic response. Obviously distinction between the activation and translocation steps is essential, and insight with respect to the mechanism (s) underlying these processes is crucial to our understanding of how hormonal information is transmitted inside the target cell. Numerous comprehensive treatises that review various aspects of the physiology and pharmacology of glucocorticoids and the role of receptors in mediating specific responses in a wide range of target tissues have been published (31, 59, 91, 143, 167, 193, 218). In the present review we attempt to avoid duplication of this information and focus our attention on various biochemical and physiological aspects of glucocorticoid-receptor activation. We try to integrate information published by numerous laboratories and