2007 Fiscal Year Final Research Report Summary
The analysis of molecular mechanism for IRS-1 ubiquitination by nitric oxide
| Project/Area Number |
18591517
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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 |
Digestive surgery
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| Research Institution | Kumamoto University |
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Principal Investigator |
SUGITA Hiroki Kumamoto University, University Hospital, Lecturer (30398218)
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| Co-Investigator(Kenkyū-buntansha) |
BABA Hideo Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Professor (20240905)
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| Project Period (FY) |
2006 – 2007
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| Keywords | nitric oxide / TRS(insulin receptor substrate)-1 / IGF(insulin like growth factor)-1 / insulin / ubiquitin / Akt / pancreatic cancer / GSK(glvcogen svnthase kinase)-3 |
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| Research Abstract |
(1) The effects of nitric oxide on IGF-R/1RS-1 /PI3-K/Akt pathway and MAPK pathway in cancer cells.
Nitric oxide (NO) donor down-regulated insulin/IGF signal including IRS-1, Akt, and GSK-3 in MIAPaCa-2 cells (derived from pancreatic cancer). On the other hand, NO donor up-regulated the phosphorylation of Erk 1/2.
(2) IRS-1 ubiquitination by NO donor
Protease inhibitor completely inhibited the degradation of IRS-1 protein by NO in MIAPaCa-2. The result suspected that NO regulated the ubiquitination and the degradation of IRS-1 protein in MIAPaCa-2. We produced the some constructs of IRS-1 delation mutants, and made the MIAPaCa-2 express them. Then, we found out the important site for IRS-I protein degradation by NO.
(3) The effects of NO on cancer proliferation
NO down-regulated the cell growth in some cancer cell lines.
We performed the cloning of stable cell lines; MIAPaCa-2 over-expressing IRS-1 wild type protein, MIAPaCa-2 over-expressing IRS-1 dominant negative. The cell line, over-expressing IRS-1 wild type protein, show high seed for cell growth, and greater sensitivity for NO. On the other hand, cell line, over-expressing IRS-1 dominant negative, show low speed of cell growth, and smaller sensitivity for NO. These results indicates that NO down-regulates IGF signal by the depression of IRS-1 protein. That may be one of the mechanisms for the down-regulation of cancer proliferation by NO.
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