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共激活剂1α的蛋白质稳定性、亚核区室化和共激活剂功能的分子内控制过氧化物酶体增殖物激活受体γ共激活剂(PGC)-1是能量代谢的关键转录调节因子。 PGC-1α 存在于整个核质中，并被迅速破坏。蛋白酶体抑制后，PGC-1α 形成不溶性多泛素化聚集体，依赖于 C 末端富含精氨酸-丝氨酸结构域和隐式异位表达 C 的完整性。 -PGC-1α末端片段自主泛素化并与早幼粒细胞白血病聚集含有两个 PEST 样基序的 N 端区域的合作对于防止多泛素化 PGC-1α 的聚集和降解来说是必需的，从而负向控制 C 端区域的聚集特性。调节 PGC-1α 的蛋白质周转和核内区室化 PGC-1α C 末端片段的外源表达干扰全长 PGC-1α 的降解我们得出结论，PGC-1α 功能通过该蛋白的几个不同结构域之间的分子内合作在多个步骤中受到严格调节。HEXIM-1 减轻缺氧引起的右心室肥大HEXIM-1 是 Cdk9 的内源性抑制剂。为了检查 Cdk9 抑制对心脏肥大发展的影响，我们通过转基因过表达 Cdk9 活性的功能丧失模型HEXIM-1。心脏特异性HEXIM-1 TG小鼠和野生型同窝小鼠相比，HEXIM-1 TG小鼠因缺氧而产生的右心室肥大程度较轻。