| Project/Area Number |
18590300
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Keio University (2007)
Kumamoto University (2006) |
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Principal Investigator |
KUNINAKA Shinji Keio University, School of Medicine, Instructor (10404336)
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| Co-Investigator(Kenkyū-buntansha) |
SAYA Hideyuki Keio University, School of Medicine, Professor (80264282)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,880,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Omi / HtrA2 protease / WARTS / Latsl kinase / 胸腺 / 脾臓 |
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| Research Abstract |
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.
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