Signaling within a coactivator complex: Methylation of SRC-3/AIB1 is a molecular switch for complex disassembly
Signaling within a coactivator complex: Methylation of SRC-3/AIB1 is a molecular switch for complex disassembly
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DOI：
10.1128/mcb.00568-06
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发表时间：
2006-11-01
影响因子：
5.3
通讯作者：
O'Malley, Bert W.
中科院分区：
文献类型：
--
作者：
Feng, Qin;Yi, Ping;O'Malley, Bert W.
最近的研究表明，类固醇受体介导的转录起始是一个涉及多轮辅激活子组装和拆卸的循环过程。类固醇受体辅激活因子3（SRC-3）辅激活因子磷酸化已被证明可以调节辅激活因子复合物的组装，但触发辅激活因子分解的机制尚不清楚。在这项研究中，我们提供了体外和体内的证据表明，SRC辅激活因子家族的成员作为底物的酶辅激活因子辅激活因子相关的精氨酸甲基转移酶1（CARM 1）。SRC-3的甲基化定位于其CARM 1结合区的精氨酸，并与雌激素受体α介导的转录降低相关，如基于细胞的和体外转录测定所示。与这一发现一致，我们证明甲基化促进SRC-3/CARM 1辅激活因子复合物的解离。SRC-3的甲基化受MCF 7细胞中雌激素信号的调节，并作为SRC-3转录辅激活因子复合物分解的分子开关。我们认为CARM 1是一种双功能的共激活因子，因为它不仅通过修饰核心组蛋白尾部来激活转录，而且通过分解共激活因子复合物来终止激素信号传导。
Recent studies indicate that steroid receptor-mediated transcriptional initiation is a cyclical process involving multiple rounds of coactivator assembly and disassembly. Steroid receptor coactivator 3 (SRC-3) coactivator phosphorylation has been shown to regulate coactivator complex assembly, but the mechanisms by which coactivator disassembly is triggered are not well understood. In this study, we provide in vitro and in vivo evidence that members of the SRC coactivator family serve as substrates for the enzymatic coactivator coactivator-associated arginine methyltransferase 1 (CARM1). Methylation of SRC-3 was localized to an arginine in its CARM1 binding region and correlated with decreased estrogen receptor alpha-mediated transcription, as seen with both cell-based and in vitro transcription assays. Consistent with this finding, we demonstrated that methylation promotes dissociation of the SRC-3/CARM1 coactivator complex. Methylation of SRC-3 is regulated by estrogen signaling in MCF7 cells and serves as a molecular switch for disassembly of the SRC-3 transcriptional coactivator complex. We propose that CARM1 is a dual-function coactivator, as it not only activates transcription by modifying core histone tails but also terminates hormone signaling by disassembly of the coactivator complex.