Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action.
Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action.
复制标题
DOI：
--
复制
发表时间：
1997
期刊：
影响因子：
--
通讯作者：
H. Shibata;T. Spencer;S. Oñate;G. Jenster;S. Tsai;M. Tsai;B. O’Malley
中科院分区：
文献类型：
--
作者：
H. Shibata;T. Spencer;S. Oñate;G. Jenster;S. Tsai;M. Tsai;B. O’Malley
类固醇/甲状腺激素受体是配体依赖性转录因子，其通过作为同源二聚体或异源二聚体与其同源DNA反应元件结合以调节靶基因的转录来调节生长、发育和稳态的各个方面。类固醇/甲状腺激素受体的反式激活涉及位于受体远端羧基末端的保守AF-2结构域。辅因子的存在，称为辅激活子或适配器，首先是由孕激素受体和雌激素受体之间的转录压制提出的。辅阻遏物也被假定有助于无配体甲状腺激素受体（TR）的沉默功能。酵母双杂交系统和Far-Western印迹已被用来确定几个蛋白质的类固醇/甲状腺激素受体超家族的成员在配体敏感的方式相互作用。我们的实验室克隆了第一个功能性共激活因子，称为类固醇受体共激活因子-一（SRC-1），这似乎是一个通用的共激活因子的所有类固醇受体测试和增强类固醇激素依赖性靶基因的反式激活。随后，报道了更多推定的共激活因子，包括SRC-1相关蛋白，TIF 2和GRIP 1，以及其他推定的和不相关的共激活因子，如ARA 70，Trip 1，RIP 140和TIF 1。此外，另一种共激活因子CREB结合蛋白（CBP）已被证明可增强类固醇受体依赖性靶基因转录。CBP和SRC-1相互作用并协同增强ER和PR的转录激活。因此，CBP，SRC-1和配体类固醇受体组成的三元复合物可能会形成，以增加乳腺癌应答基因转录的速率。类似地，TR和视黄酸受体（RAR）的共阻遏物，如SMRT和N-CoR，已经被鉴定。未配体的TR和RAR已被证明抑制基础启动子活性;这种由未配体的受体引起的靶基因转录的沉默是由这些共阻遏物介导的。总的来说，现有的证据支持以下模型的类固醇反应基因转录。在结合激动剂后，受体改变其在配体结合结构域中的构象，这使得能够募集共激活因子，这允许受体更有效地与基础转录机制相互作用并激活转录。相反，拮抗剂的结合诱导受体的不同构象变化。尽管一些拮抗剂结合的受体可以二聚化并结合到其同源DNA元件上，但它不能去除相关的辅阻遏物，这导致与基础转录机制的非生产性相互作用。类似地，TR和RAR在不存在配体的情况下与辅阻遏物缔合，从而导致与沉默靶基因表达的转录机制的负相互作用。在混合的激动剂/拮抗剂（例如4-羟基他莫昔芬）的情况下，基因转录的激活可取决于细胞中共激活子和共阻遏子的相对比率或细胞特异性因子，其决定不同化合物的相对激动或拮抗潜力。这些共激活子和共阻遏子似乎充当调节对靶基因表达的应答的转录调节的加速器和/或制动器。因此，最近发现的辅激活子和辅抑制子扩大了我们的知识类固醇受体的作用机制。
Steroid/thyroid hormone receptors are ligand-dependent transcription factors that regulate diverse aspects of growth, development, and homeostasis by binding as homodimers or heterodimers to their cognate DNA response elements to modulate transcription of target genes. Transactivation by steroid/ thyroid hormone receptors involves a conserved AF-2 domain located in the distal carboxy-terminus of the receptors. The existence of co-factors, termed co-activators or adapters, was first suggested by transcriptional squelching between progesterone receptors and estrogen receptors. Co-repressors were also postulated to contribute to the silencing function of unliganded thyroid hormone receptor (TR). The yeast two-hybrid system and Far-Western blotting have been used to identify several proteins that interact with members of the steroid/thyroid hormone receptor superfamily in a ligand-sensitive manner. Our laboratory cloned the first functional co-activator, termed steroid receptor co-activator-one (SRC-1), that appears to be a general co-activator for all steroid receptors tested and enhances transactivation of steroid hormone-dependent target genes. Subsequently, many more putative co-activators have been reported, including the SRC-1 related proteins, TIF2 and GRIP1, and other putative and unrelated co-activators such as ARA70, Trip1, RIP140, and TIF1. In addition, another co-activator, CREB-binding protein (CBP), has been shown to enhance steroid receptor-dependent target gene transcription. CBP and SRC-1 interact and synergistically enhance transcriptional activation by the ER and PR. Therefore, a ternary complex-consisting of CBP, SRC-1, and liganded steroid receptors-may form to increase the rate of hormone-responsive gene transcription. Similarly, co-repressors, such as SMRT and N-CoR, for TR and retinoic acid receptors (RAR) have been identified. The unliganded TR and RAR have been shown to inhibit basal promoter activity; this silencing of target gene transcription by unliganded receptors is mediated by these co-repressors. Collectively, available evidence supports the following model of steroid-responsive gene transcription. Upon binding of agonist the receptor changes its conformation in the ligand-binding domain that enables recruitment of co-activators, which allows the receptor to interact with the basal transcriptional machinery more efficiently and to activate transcription. In contrast, binding of antagonists induces a different conformational change in the receptor. Although some antagonist-bound receptor can dimerize and bind to its cognate DNA element, it fails to dislodge the associated co-repressors, which results in a nonproductive interaction with the basal transcriptional machinery. Similarly, the TR and RAR associate with co-repressors in the absence of ligand, thereby resulting in a negative interaction with the transcriptional machinery that silences target gene expression. In the case of mixed agonist/antagonists, such as 4-hydroxytamoxifen, activation of gene transcription may depend on the relative ratio of co-activators and co-repressors in the cell or cell-specific factors that determine the relative agonistic or antagonistic potential of different compounds. These co-activators and co-repressors appear to act as an accelerator and/or a brake that modulates transcriptional regulation of hormone-responsive target gene expression. Thus, the recent discovery of co-activators and co-repressors expands our knowledge of the mechanisms of steroid receptor action.