| Project/Area Number |
21590316
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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 |
General medical chemistry
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| Research Institution | Osaka City University |
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Principal Investigator |
KOJIMA Hirotada 大阪市立大学, 大学院・医学研究科, 講師 (40336772)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAJIMA Koichi 大阪市立大学, 大学院・医学研究科, 教授 (00227787)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | サイトカイン / 細胞老化 / がん / シグナル伝達 |
|---|
| Research Abstract |
Normal cells undergo senescence in response to various stresses, such as DNA damage and certain cytokines. One such cytokine, interleukin-6 (IL-6), a multifunctional cytokine, can act on multiple lineages of cells combination with soluble IL-6 receptor α (sIL-6Rα) to induce cell proliferation, differentiation and even promotion of tumorigenesis. We studied the molecular mechanisms by which IL-6 and sIL-6Rα cause premature senescence using primary human fibroblasts. Stimulation of fibroblasts cells with IL-6/sIL-6Rα sequentially caused generation of reactive oxygen species (ROS) as early as day 1, followed by DNA damage, p53 accumulation, and finally senescence. STAT3 was required for the early and late events leading to senescence, including the early-phase increase of ROS and senescence-associated secretary phenotype occurring 4 days after IL-6/sIL-6Ra stimulation. Interestingly, Insulin-like growth factor-binding protein 5 (IGFBP-5) secreted into the supernatants was identified as the STAT3-downstream molecule responsible for the IL-6/STAT3-induced ROS generation and premature senescence. IGFBP-5 was consistently expressed from the initial phase through the entire senescence process, the profile being quite different from that of senescence-associated secretary phenotype. Thus, IL-6/sIL-6R? forms a senescence-inducing circuit involving the STAT3?IGFBP5 axis as a key triggering and reinforcing component.
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