| Project/Area Number |
15209013
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Yokohama City University Graduate School of Medical Science |
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Principal Investigator |
OHNO Shigeo Yokohama City University Graduate School of Medical Science, Department of Molecular Biology, Professor, 大学院・医学研究科, 教授 (10142027)
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| Co-Investigator(Kenkyū-buntansha) |
HIRAI Syu-ichi Yokohama City University Graduate School of Medical Science, Department of Molecular Biology, Associate Professor, 大学院・医学研究科, 助教授 (80228759)
SUZUKI Atsushi Yokohama City University Graduate School of Medical Science, Department of Molecular Biology, lecturer, 大学院・医学研究科, 講師 (00264606)
MIZUNO Keiko Yokohama City University School of Medicine, Department of Molecular Biology, Assistant Professor, 医学部, 助手 (90221803)
AKIMOTO Kazunori Yokohama City University School of Medicine, Department of Molecular Biology, Assistant Professor, 医学部, 助手 (70285104)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥47,320,000 (Direct Cost: ¥36,400,000、Indirect Cost: ¥10,920,000)
Fiscal Year 2004: ¥24,180,000 (Direct Cost: ¥18,600,000、Indirect Cost: ¥5,580,000)
Fiscal Year 2003: ¥23,140,000 (Direct Cost: ¥17,800,000、Indirect Cost: ¥5,340,000)
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| Keywords | nonsense mutaion / mRNA degradation / mRNA surveillance / P53 / protein kinase / PIK remated protein kinase / RNA helicase / ATPase |
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| Research Abstract |
Eukaryotes possess a system termed 'nonsense-mediated mRNA decay' (NMD) or 'mRNA surveillance', by which aberrant mRNAs with premature termination codons (PTCs) are removed from cells, thereby protecting them from accumulation of nonfunctional or potentially harmful polypeptides. Thus, Nonsense-mediated mRNA decay (NMD) is a quality control mechanism of mRNA. Proteins required for NMD (UPF1,2,3, and SMG-1, SMG-5,6,7) have been identified initially from yeast and C. elegans genetics but recent experiments on mammlas are revealing the physiological meaning and the molecular mechanism of NMD in human cells. Central player of NMD is the putative surveillance complex that recognizes PTC-containing mRNA in a manner dependent on both splicing and translation. Components of the surveillance complex include UPF1, an RNA helicase, and UPF2 and UPF3. SMG-1 phosphorylates UPF1 and SMG and SMG-7 help dephosphorylation of UPF1 by PP2A. Importantly, both phosphorylation by SMG-1 and dephosphorylation by PP2A of UPF1 are required for NMD in human cells. Biochemical experiments revealed that phosphorylation and dephosphorylation of UPF1 by SMG-1 and PP2A, respectively, cause the remodeling of the surveillance complex. These observations supports the idea raised by a series of molecular genetic experiments that SMG-1-mediated phsphorylation fo UPF1 is the critical step during the recognition of PTC-containing mRNA by the surveillance complex.
Although NMD is primarily the protective mechanism, there are many cases of genetic diseases that are exacerbated by NMD. Thus, suppression of NMD might be one of the potential therapeutic approach against gene mutations that generates nonsense mRNA. We now have the tools that can modulate NMD, it is now possible to examine the contributuin of NMD in a variety of cases that involves NMD. Genetic diseases and cancer are the primary candidates for such experiments that aims to suppress NMD through inhibition of SMG-1.
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