| Project/Area Number |
15370080
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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 |
Molecular biology
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| Research Institution | National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology |
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Principal Investigator |
MOTOYAMA Noboru National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Department of Geriatric Research, Section Chief, (研究所)・老年病研究部, 室長 (50277282)
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| Co-Investigator(Kenkyū-buntansha) |
SAWA Hirofumi Hokkaido University Graduate School of Medicine, Laboratory of Molecular & Cellular Pathology, Associate Professor, 大学院・医学研究科, 助教授 (30292006)
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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 |
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2004: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 2003: ¥7,200,000 (Direct Cost: ¥7,200,000)
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| Keywords | Aging / DNA damage / Chk2 / p53 / FOXO / SIRT1 / apoptosis / oxidative stress / DNA傷害 / リン酸化 / アセチル化 |
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| Research Abstract |
Recent identification of human genes responsible for premature aging syndromes has revealed that the encoded proteins function in the cellular response to DNA damage and thereby contribute to the maintenance of genomic integrity. These findings thus suggest that defects in the DNA damage response can result in aging as well as in cancer. We investigated that the mechanisms of the activation and the function of the Chk2-p53 pathway and of the FOXO pathway in cells subjected to DNA damage as well as in the relations of these signaling pathways to aging and cancer. Here we have shown that Chk2 regulates p53 protein stabilization by phosphorylating Mdm2 on Ser78 and that Chk2 regulates both transcription-independent and transcription-dependent mechanisms of p53-mediated apoptosis by stabilizing p53 and by increasing its transcriptional regulatory activity. Moreover, we have found that ATM-Chk2-p53-dependent signaling pathway triggered by DNA damage is dispensable for the activation of stress-induced premature senescence to IR or oxidative stress. These results suggest that both ATM-Chk2-p53-dependent and -independent signaling pathway, apoptosis and senescence, act as a "security gate" to prevent neoplastic transformation. However, as a side effect, hyperactivity of the ATM-Chk2-p53 pathway caused apoptosis may also compromises organism homeostasis and eventually results in aging. FOXO family regulates various biological activities, including cell cycle progression, the cellular response to oxidative stress, DNA repair, and apoptosis, suggesting that FOXO also contributes genomic integrity. Furthermore, we have shown that mammalian SIRT1 interacts physically, functionally, and physiologically with FOXO, suggesting that FOXO family protein and SIRTl may cooperate to extend life span in response to restriction of caloric intake in mammals by preventing DNA damage accumulation.
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