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INVESTIGATION OF MECHANISM OF PREVENTION OF ATHEROSCLEROSIS BY SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERM)

选择性雌激素受体调节剂（SERM）预防动脉粥样硬化的机制研究

基本信息

批准号：
13470219
负责人：
SARUTA Takao
金额：
$ 3.2万
依托单位：
KEIO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470219/
关键词：
Estrogen Receptor coactivator COUP-TF FHL2 SERM FHL-2 COUP-TFI 転写共役因子 coactivator corepressor 核内受容体コリプレッサー

项目摘要

1) We screened Estrogen Receptor α (ERα)-interacting proteins using yeast two hybrid system from a human heart cDNA library. We successfully identified LIM-only-domain containing factor FHL2 and Sumoylation enzymes Ubc9 and PIAS1 as ERα-interacting proteins in an estradiol-sensitive manner. FHL2 is highly expressed in cardiac muscle specifically, and reported that it interacts with several transcription factors, such as Androgen Receptor, AP-1, CREB and CREM. This is the first report of FHL2 as ERα interacting protein. FHL2 interacts with ERα in the presence of 17β-estradiol, but there was no significant influence on transcriptional activity through ERα by transient transfection assay using an ERE-E 1b-Luciferase reporter. Given the fact that FHL2 is specifically highly expressed in the cardiac muscle, FHL2 is likely to be involved in the pathophysiology of cardiac hypertrophy.2) We have previously identified SUMOylation enzymes Ubc9 and PIAS1 as COUP-TFI interacting proteins. In the present project, we also identified them as ERα-interacting proteins. We investigated the role of these proteins in ER-mediated transcription, and found that they function as transcriptional coactivators of ERα. Since a recent report showed that COUP-TFI activates ERα through phospholylation of Ser118 of ERα, it is conceivable that Ubc9, PIAS1 and COUP-TFI form ternary complex to modulate ERα transcriptional activities.

1)利用酵母双杂交系统从人心脏cDNA文库中筛选雌激素受体α（ERα）相互作用蛋白。我们成功地鉴定了含LIM-only-domain的因子FHL 2和Sumoylation酶Ubc 9和PIAS 1作为雌激素敏感的ERα相互作用蛋白。FHL 2在心肌特异性表达，与雄激素受体、AP-1、CREB、CREM等转录因子相互作用。这是FHL 2作为ERα相互作用蛋白的首次报道。在17β-雌二醇存在下，FHL 2与ERα相互作用，但通过使用ERE-E 1b-荧光素酶报告基因的瞬时转染试验，FHL 2通过ERα对转录活性没有显著影响。鉴于FHL 2在心肌中特异性高表达的事实，FHL 2可能参与心脏肥大的病理生理学。2）我们先前已经鉴定了SUMO化酶Ubc 9和PIAS 1作为COUP-TFI相互作用蛋白。在本项目中，我们还将它们鉴定为ERα相互作用蛋白。我们研究了这些蛋白在ER介导的转录中的作用，发现它们是ERα的转录辅激活因子。最近的研究表明COUP-TFI通过磷酸化ERα的Ser 118激活ERα，推测Ubc 9、PIAS 1和COUP-TFI可能形成三元复合物调控ERα的转录活性。