Pratt W B, Dalman F C, Meshinchi S, Scherrer L C
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
Nihon Naibunpi Gakkai Zasshi. 1990 Dec 20;66(12):1185-97. doi: 10.1507/endocrine1927.66.12_1185.
In this minireview we summarize evidence that the association of the glucocorticoid receptor (GR) with hsp90 may determine three functional states of the receptor. First, there is a direct correlation between hsp90 binding to the receptor and repression of DNA binding activity. Temperature-dependent dissociation of hsp90 from the cytosolic GR-hsp90 complex is promoted by hormone with simultaneous conversion of the receptor to the DNA binding state. GR that is translated in rabbit reticulocyte lysate binds to hsp90 at or near the termination of receptor translation and is in the non-DNA-binding form. Second, there is a direct correlation between binding of the immunopurified GR to hsp90 and the presence of a high affinity steroid binding conformation of the receptor. GR translated in reticulocyte lysate binds steroid with high affinity, but GR translated in wheat germ extract is not bound to hsp90, does not bind steroid with high affinity, and is in the DNA-binding form. When immunopurified, hsp90-free GR is incubated with rabbit reticulocyte lysate, hsp90 associates with the receptor and high affinity steroid binding capacity is completely reactivated. Third, there is a correlation between binding of hsp90 to steroid receptors and their retention in an inactive "docking" state until the binding of hormone in the intact cell triggers a progression to high affinity nuclear binding sites where the primary events involved in transcriptional activation occur. In contrast to the receptors that are retained in the docking state, the unliganded thyroid hormone receptor proceeds directly to high affinity nuclear binding sites. Consistent with this difference in behavior, the thyroid hormone receptor is translated in reticulocyte lysate in its DNA binding form and is not associated with hsp90.
在本综述中，我们总结了相关证据，表明糖皮质激素受体（GR）与热休克蛋白90（hsp90）的结合可能决定受体的三种功能状态。首先，hsp90与受体的结合和DNA结合活性的抑制之间存在直接相关性。激素可促进hsp90从细胞质GR - hsp90复合物中温度依赖性解离，同时受体转变为DNA结合状态。在兔网织红细胞裂解物中翻译的GR在受体翻译接近终止时与hsp90结合，处于非DNA结合形式。其次，免疫纯化的GR与hsp90的结合和受体高亲和力类固醇结合构象的存在之间存在直接相关性。在网织红细胞裂解物中翻译的GR以高亲和力结合类固醇，但在小麦胚芽提取物中翻译的GR不与hsp90结合，不以高亲和力结合类固醇，且处于DNA结合形式。当免疫纯化的无hsp90的GR与兔网织红细胞裂解物一起孵育时，hsp90与受体结合，高亲和力类固醇结合能力完全恢复。第三，hsp90与类固醇受体的结合及其在无活性“对接”状态的保留之间存在相关性，直到完整细胞中激素的结合触发其向高亲和力核结合位点的转变，在该位点发生转录激活的主要事件。与保留在对接状态的受体不同，未结合配体的甲状腺激素受体直接进入高亲和力核结合位点。与这种行为差异一致，甲状腺激素受体在网织红细胞裂解物中以其DNA结合形式翻译，且不与hsp90相关。
