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Development of novel therapy for heart failure using Cdk9 as a target molecule

使用 Cdk9 作为靶分子开发心力衰竭新疗法

基本信息

批准号：
18390239
负责人：
SANO Motoaki
金额：
$ 11.36万
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：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor gamma coactivator 1alphaPeroxisome proliferator-activated receptor gamma coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1alpha is a short lived and aggregation-prone protein. PGC-1alpha localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1alpha formed insoluble polyubiquitinated aggregates. Ubiquitination of PGC-1alpha depended on the integrity of the C terminus-containing arginine-serine-rich domains and an RNA recognition motif. Interestingly, ectopically expressed C-terminal fragment of PGC-1alpha was autonomously ubiquitinated and aggregated with promyelocytic leukemia protein. Cooperation of the N-terminal region containing two PEST-like motifs was required for prevention of aggregation and targeti … More ng of the polyubiquitinated PGC-1alpha for degradation. This region thereby negatively controlled the aggregation properties of the C-terminal region to regulate protein turnover and intranuclear compartmentalization of PGC-1alpha Exogenous expression of the PGC-1alpha C-terminal fragment interfered with degradation of full-length PGC-1alpha and enhanced its coactivation properties. We concluded that PGC-1alpha function is critically regulated at multiple steps via intramolecular cooperation among several distinct structural domains of the protein.HEXIM-1 alleviated hypoxia-induced right ventricular hypertrophyHEXIM-1 is an endogenous inhibitor of Cdk9. To examine the effect of Cdk9 inhibition on the development of cardiac hypertrophy, we developed loss of function model of Cdk9 activity by transgenic over-expression of HEXIM-1. Cardiac-specific HEXIM-1 TG mice and wild-type littermates were subjected to hypoxia (11% O_2). Right ventricular hypertrophy produced by hypoxia was milder in HEXIM-1 TG mice compared to wild-type littermates. Less

过氧化物酶体增殖物激活受体γ辅激活因子1 α的蛋白质稳定性、亚核区室化和辅激活因子功能的分子内控制过氧化物酶体增殖物激活受体γ辅激活因子（PGC）-1是能量代谢的关键转录调节因子。在这里，我们发现PGC-1 α是一种寿命短且易于聚集的蛋白质。PGC-1 α定位于整个核质中，并通过泛素-蛋白酶体途径被迅速破坏。在蛋白酶体抑制后，PGC-1 α形成不溶性聚泛素化聚集体。PGC-1 alpha的遍在化取决于含有C末端的富含精氨酸-丝氨酸的结构域和RNA识别基序的完整性。有趣的是，异位表达的PGC-1 α的C-末端片段被自主泛素化并与早幼粒细胞白血病蛋白聚集。含有两个PEST样基序的N-末端区域的合作是防止聚集和靶向的必要条件。 ...更多信息 ng的聚泛素化PGC-1 α用于降解。因此，该区域负控制C-末端区域的聚集特性，以调节蛋白质周转和PGC-1 α的核内区室化。PGC-1 α C-末端片段的外源表达干扰全长PGC-1 α的降解，并增强其共激活特性。我们的结论是，PGC-1 α的功能是通过几个不同的结构域之间的分子内合作，在多个步骤中进行关键性调节。HEXIM-1减轻缺氧诱导的右心室肥大HEXIM-1是Cdk 9的内源性抑制剂。为了检测Cdk 9抑制对心脏肥大发展的影响，我们通过HEXIM-1的转基因过表达开发了Cdk 9活性的功能丧失模型。心脏特异性HEXIM-1 TG小鼠和野生型同窝小鼠经受缺氧（11%O_2）。与野生型同窝小鼠相比，HEXIM-1 TG小鼠中缺氧引起的右心室肥大较轻。少