The role of heat shock proteins in regulating the function, folding, and trafficking of the glucocorticoid receptor.
The role of heat shock proteins in regulating the function, folding, and trafficking of the glucocorticoid receptor.
复制标题
DOI：
--
复制
发表时间：
1993-10
期刊：
影响因子：
--
通讯作者：
W. Pratt
中科院分区：
文献类型：
--
作者：
W. Pratt
类固醇受体是直接信号转导系统，其中受体通过结合激素接收信号输入，然后以其类固醇激活形式结合基因组中的增强子序列，在那里它改变特定基因的转录速率（1）。受体的独立结构域负责信号接收和随后的DNA结合，并且COOH末端中的激素结合结构域（HBD）的缺失产生作为组成型转录激活剂的受体（2）。因此，HBD执行三种功能，即它抑制受体的转录激活活性，它结合激素，并且它决定受体功能的酶调节的去抑制。HBD还决定糖皮质激素受体（GR）与hsp 9 O的紧密结合（3），这种结合对于受体的正确折叠和功能至关重要（4-6）。我们对类固醇受体与热休克蛋白90相互作用的重要性的认识是从近三十年来对胞质受体的研究中发展起来的。在1966年对类固醇受体结构的最早研究中，Toft和Gorski（7）证明了细胞溶质提取物中存在大的-9 S形式的雌激素受体。随后发现，这种大的类固醇受体形式不与DNA结合，但可以转化为具有DNA结合活性的4S形式（4）。孕激素能稳定受体的非DNA结合形式（8），这一发现促进了9 S孕酮受体的纯化和特异性识别未转化状态的抗体的制备（9）。
The steroid receptors are direct signal transduction systems in which the receptor both receives the signal input by binding the hormone and then, in its hormone-activated form, binds to en- hancer sequences in the genome, where it alters the transcription rates of specific genes (1). Separate domains of the receptors are responsible for signal reception and subsequent DNA binding, and deletion of the hormone binding domain (HBD) in the COOH ter- minus yields receptors that are constitutive activators of transcription (2). Thus, the HBD performs three functions in that it re- presses the transcriptional activating activity of the receptor, it binds hormone, and it determines hormone-regulated derepression of receptor function. The HBD also determines the tight binding of the glucocorticoid receptor (GR) to hsp9O (3), an association that is critical for proper folding and function of the receptor (4-6). Our appreciation of the importance of the steroid receptor-hsp90 interaction developed from the study of cytosolic receptors over nearly three decades. In one of the earliest studies of steroid receptor structure in 1966, Toft and Gorski (7) demonstrated the existence of a large -9 S form of the estrogen receptor in cytosolic extracts. It subsequently became clear that this large form of the steroid receptors does not bind to DNA but can be transformed to a 4 S form with DNA binding activity (4). The discovery that molyb- date stabilizes the receptors in their non-DNA binding form (8) facilitated purification of the 9 S progesterone receptor and prepa- ration of an antibody that specifically recognized the untransformed state (9).