| Project/Area Number |
14380304
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE |
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Principal Investigator |
KITAGAWA Masatoshi HAMAMATSU UNIVERSITY, Medicine, Professor, 医学部, 教授 (50294971)
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| Co-Investigator(Kenkyū-buntansha) |
KITAGAWA Kyoko HAMAMATSU UNIVERSITY, Medicine, Assistant Professor, 医学部, 助手 (20299605)
UCHIDA Chiharu HAMAMATSU UNIVERSITY, Medicine, Assistant Professor, 医学部, 助手 (60223567)
ODA Toshiaki HAMAMATSU UNIVERSITY, Medicine, Associate Professor, 医学部, 助教授 (90126805)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥15,100,000 (Direct Cost: ¥15,100,000)
Fiscal Year 2003: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2002: ¥10,100,000 (Direct Cost: ¥10,100,000)
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| Keywords | Ubiquitin ligase / p27^<Kip1> / RB protein / Cell cycle / cancer / prognosis / 癌 |
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| Research Abstract |
Ubiquitin-proteasome pathway is a key system that controls cellular levels of number of proteins. This pathway is responsible not only for the degradation of short-lived proteins but also tumor suppressors, transcription factors and cell cycle proteins. Ubiquitin-protein ligases determine the substrate specificity of ubiquitination. In this study, we analyzed the molecular mechanisms of proteolytic degradation of two major tumor suppressor gene products such as p27^<Kip1> and RB protein. Fast of all, we tried to identify the ubiquitin ligase for RB protein and analyze its function in malignant transformation process (1). The other project is identification of the down-regulation mechanisms of p27^<Kip1> (2).
In this study, we demonstrated that Mdm2 promotes ubiqutination of RB protein as an ubiquitin ligase and proteasome-mediated degradation of it. Knockdown of Mdm2 significantly accumulated steady state levels of RB protein. In human lung cancer tissues, high expression of Mdm2 correlated with down regulation of RB protein. These results suggest that facilitation of degradation of RB protein by Mdm2 perturbs the tumor suppressor RB-pathway. On the other hand, we found that Cks1, a subcomponent of SCF-Skp2 ubiquitin ligase for p27-degradation, was post-translalionally regulated by ubiquitin-proteasome pathway. We also found high expression of Cks1 in human lung cancers. Therefore, altered degradation of these cell cycle proteins or tumor suppressors is thought to promote growth and malignancy of cancer.
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