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）我们使用人心心脏cDNA文库中的酵母两种混合系统筛选了雌激素受体α（ERα）互动蛋白。我们以雌二醇敏感的方式成功地将包含因子FHL2和sumoylation酶UBC9和PIAS1的LIM抑制剂ubc9和PIAS1鉴定为ERα相互作用蛋白。 FHL2在心脏肌肉中高度表达，并报道它与多种转录因子相互作用，例如雄激素受体，AP-1，CREB和CREM。这是FHL2作为ERα相互作用蛋白的第一个报告。在17β-雌二醇存在下，FHL2与ERα相互作用，但使用ERE-E 1B-荧光素酶报告基因通过瞬态翻译测定法对转录活性没有显着影响。鉴于FHL2在心脏肌肉中高度表达的事实，FHL2可能参与心脏肥大的病理生理学。2）我们先前已经将Sumoylation酶UBC9和PIAS1识别为oup-tfi相互作用的蛋白质。在本项目中，我们还将它们确定为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，并发现它们是ERα的转录共激活剂。自最近的一份报告显示，政府TFI通过ERα的Ser118的磷酸化激活ERα，因此可以想象UBC9，PIAS1和COUP-TFI形成三元复合物以调节ERα的转录活性。