GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors
GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors
复制标题
DOI：
10.1128/mcb.17.5.2735
复制
发表时间：
1997-05-01
影响因子：
5.3
通讯作者：
Stallcup, MR
中科院分区：
文献类型：
--
作者：
Hong, H;Kohli, K;Stallcup, MR
与增强子元件结合后，转录因子需要转录共激活蛋白来介导转录起始的刺激，对类固醇激素受体可能的共激活蛋白的搜索导致糖皮质激素受体相互作用蛋白 1 (GRIP1) 的鉴定，从小鼠大脑 cDNA 文库中分离出 GRIP1 的完整编码序列，包含 1,462 个密码子的开放阅读框，GRIP1 是 随后鉴定的人类蛋白质转录中间因子 2 (TIF2) 的可能直向同源物，并且与类固醇受体辅激活因子 1 (SRC-1) 部分同源，全长 GRIP1 以激素依赖性方式与所有五种类固醇受体的激素结合域 (HBD) 相互作用，并且还与 II 类核受体的 HBD 相互作用，包括甲状腺受体 α、维生素 D 受体、视黄酸受体 α 和类视黄醇 X 受体 α。与激动剂相反，糖皮质激素拮抗剂不会促进糖皮质激素受体与 GRIP1 之间的相互作用。在酵母细胞中，GRIP1 显着增强了含有与 GAL4 DNA 结合域融合的任何上述受体的 HBD 的蛋白质的转录激活功能，从而充当它们的转录共激活因子。这一发现与之前关于 TIF2 和 SRC-I 的报道形成鲜明对比，后者在哺乳动物细胞中仅增强了与其物理相互作用的类固醇和核受体子集的反式激活活性。 GRIP1 还增强了完整糖皮质激素受体、雌激素受体和盐皮质激素受体的激素依赖性反式激活活性。糖皮质激素受体截短和点突变体的实验表明，GRIP1 与糖皮质激素受体的 C 端 AF-2 但不与 N 端 AF-1 反式激活结构域相互作用并增强其活性。这些结果证明 直接表明 AF-1 和 AF-2 结构域通过不同的机制完成其反式激活活动：AF-2 需要 GRIP1 作为共激活剂，但 AF-1 不需要。
After binding to enhancer elements, transcription factors require transcriptional coactivator proteins to mediate their stimulation of transcription initiation, A search for possible coactivators for steroid hormone receptors resulted in identification of glucocorticoid receptor interacting protein 1 (GRIP1), The complete coding sequence for GRIP1, isolated from a mouse brain cDNA library, contains an open reading frame of 1,462 codons, GRIP1 is the probable ortholog of the subsequently identified human protein transcription intermediary factor 2 (TIF2) and is also partially homologous to steroid receptor coactivator 1 (SRC-1), The full-length GRIP1 interacted with the hormone binding domains (HBDs) of all five steroid receptors in a hormone-dependent manner and also with HBDs of class II nuclear receptors, including thyroid receptor alpha, vitamin D receptor, retinoic acid receptor alpha, and retinoid X receptor alpha. In contrast to agonists, glucocorticoid antagonists did not promote interaction between the glucocorticoid receptor and GRIP1. In yeast cells, GRIP1 dramatically enhanced the transcriptional activation function of proteins containing the HBDs of any of the above-named receptors fused to the GAL4 DNA binding domain and thus served as a transcriptional coactivator for them. This finding contrasts with previous reports of TIF2 and SRC-I, which in mammalian cells enhanced the transactivation activities of only a subset of the steroid and nuclear receptors that they physically interacted with. GRIP1 also enhanced the hormone-dependent transactivation activity of intact glucocorticoid receptor, estrogen receptor, and mineralocorticoid receptor, Experiments with glucocorticoid receptor truncation and point mutants indicated that GRIP1 interacted with and enhanced the activity of the C-terminal AF-2 but not the N-terminal AF-I transactivation domain of the glucocorticoid receptor, These results demonstrate directly that AF-1 and AF-2 domains accomplish their transactivation activities through different mechanisms: AF-2 requires GRIP1 as a coactivator, but AF-I does not.