2007 Fiscal Year Final Research Report Summary
Mechanism of metastasis inhibition by LyGDI cleaved by caspase-1
| Project/Area Number |
18590706
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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 |
Gastroenterology
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| Research Institution | Kanazawa Medical University |
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Principal Investigator |
MEADA Masayo Kanazawa Medical University, School of Medicine, Senior Assistant Professor (30199632)
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| Co-Investigator(Kenkyū-buntansha) |
OTA Takahide Kanazawa Medical University, Medical Research Institute, Associate Professor (10152141)
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| Project Period (FY) |
2006 – 2007
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| Keywords | LvGDI / RhoGDIβ / D4GDI / RhoGDI2 / Caspase-1 / Anoikis / Apoptosis / Metastasis / Colon cancer / Rho |
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| Research Abstract |
RhoGDI is a regulator for Rho family small G proteins and at least three kinds of RhoGDIs are known. LyGDI (D4GDI/RhoGDIb/RhoGDI2) is one of these RhoGDIs and characteristically has a caspase-1 cleavage site at Asp^<55>. When the expression vector of LyGDI-Δ55, which is an expected product upon cleavage by caspase-1, are introduced into metastatic mouse tumor cells (1-1src), the forced expression of LyGDI-M5 enhanced the anoikis (detachment-induced apoptosis) sensitivity and decreased the metastatic ability to the lung. Accompanied with these changes, the membrane localization of FAK (focal adhesion kinase) was decreased. LyGDI is expressed at high level in hematopoietic cells, however we found that LyGDI also expressed in several human colon cancer cell lines. Therefore, we attempted to examine the role of LyGDI-Δ55 in the anoikis in the human colon cancer cell lines. We used two cell lines, HT29 and SW480. HT29 cells are resistant to anoikis and express LyGDI at high level while SW480 cells are sensitive to anoikis and express LyGDI at low level. We examined whether LyGDI was cleaved by caspase-1 upon anoikis induction, but we could not observe the cleavage of LyGDI by caspase-1. To further confirm the cleavage of LyGDI by caspase-1 we incubated a purified human LyGDI with caspase-1 in vitro, but the cleavage of LyGDI by caspase-1 was extremely slight. These observations strongly suggested that LyGDI was not cleaved by caspase-1 at Asp^<55>. The precise cleavage site in situ is unknown, however we have found LyGDI-Δ55, which lacks a N-terminal regulating region, suppressed a metastasis. Further study of the function of LyGDI-Δ55 is continued.
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