权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Analysis of serine protease Omi-mediated-signaling pathway which could affect both tumorigenesis and neurodegenerative disorder

丝氨酸蛋白酶 Omi 介导的信号通路影响肿瘤发生和神经退行性疾病的分析

基本信息

批准号：
18590300
负责人：
KUNINAKA Shinji
金额：
$ 2.48万
依托单位：
Keio University (2007)Kumamoto University (2006)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590300/
关键词：
Omi HtrA2 protease WARTS Latsl kinase 胸腺脾臓

项目摘要

It is well known that apoptosis is a major safeguard to tumorigenesis. The serine protease Omi was initially regarded as a proapoptotic molecule. Recent studies, however, indicate that loss of Omi protease activity increases susceptibility to stress-induced cell death, resulting neurodegenerative disorder. These complicated findings suggest that protease activity of Omi is involved not only in apoptosis but also in cellular homeostasis. However, the targets which Omi uses to mediate this novel process are unknown. Previously, we showed that WARTS (WTS)/Lats1 mitotic kinase interacts with the PDZ domain of Omi and promotes its protease activity. We now report that WTS is a substrate for Omi protease activity, thus it is not only a regulator but also a downstream target of this protease. Interaction with Omi PDZ domain is required for WTS to be proteolysed. When caspase-9-deficient mouse embryonic fibroblasts (MEFs) were treated with staurosporine, WTS was proteolysed by activated endogenous Omi without induction of cell death Therefore, protease activity of Omi and proteolysis of WTS are not necessarily required for cell death. We found that depletion of Omi from HeLa cells results in accelerated cell proliferation despite no significant change in the duration of mitosis. The depletion of WTS showed the same effect on S phase progression. Therefore, WTS proteolytic fragment(s) generated by Omi may act as an inhibitor of G1/S progression. Our data reveal a role for Omi-mediated processing of WTS in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis.

细胞凋亡是肿瘤发生的重要保障。丝氨酸蛋白酶Omi最初被认为是一种促凋亡分子。然而，最近的研究表明，Omi蛋白酶活性的丧失增加了对应激诱导的细胞死亡的易感性，导致神经退行性疾病。这些复杂的研究结果表明，Omi的蛋白酶活性不仅参与细胞凋亡，而且参与细胞内稳态。然而，Omi用于介导这一新过程的靶点尚不清楚。以前，我们发现WARTS（WTS）/Lats 1有丝分裂激酶与Omi的PDZ结构域相互作用，并促进其蛋白酶活性。我们现在报道，WTS是Omi蛋白酶活性的底物，因此它不仅是调节剂，而且是该蛋白酶的下游靶标。与Omi PDZ结构域的相互作用是WTS被蛋白水解所必需的。当用星形孢菌素处理caspase-9缺陷的小鼠胚胎成纤维细胞（MEF）时，WTS被活化的内源Omi蛋白水解而不诱导细胞死亡。因此，Omi的蛋白酶活性和WTS的蛋白水解对于细胞死亡不是必需的。我们发现，从HeLa细胞中的Omi的耗竭导致加速细胞增殖，尽管在有丝分裂的持续时间没有显着的变化。WTS的耗竭对S期进展显示出相同的效果。因此，由Omi产生的WTS蛋白水解片段可以作为G1/S进展的抑制剂。我们的数据揭示了Omi介导的WTS加工在细胞周期进程的负调控中的作用，表明Omi除了凋亡之外还有一种新的功能。