| Project/Area Number |
14370126
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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 |
Hygiene
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
SAKAI Toshiyuki Kyoto Prefectural University of Medicine, Department of Molecular-Targeting Cancer Prevention, Professor, 医学研究科, 教授 (20186993)
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| Co-Investigator(Kenkyū-buntansha) |
SOWA Yoshihiro Kyoto Prefectural University of Medicine, Department of Molecular-Targeting cancer Prevention, Lecturer, 医学研究科, 講師 (70315935)
MATSUZAKI Youichirou Kyoto Prefectural University of Medicine, Department of Molecular-Targeting Cancer Prevention, Assistant Professor, 医学研究科, 助手 (70282522)
YOSHIDA Tatsushi Kyoto Prefectural University of Medicine, Department of Molecular-Targeting Cancer Prevention, Assistant Professor, 医学研究科, 助手 (80315936)
KAMIYAMA Jun Meiji University of Oriental Medicine, Department of Surgery, Lecturer, 鍼灸学部, 講師 (20257538)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2004: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 2003: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 2002: ¥3,100,000 (Direct Cost: ¥3,100,000)
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| Keywords | butyrate / p18 / p19 / DR5 / TRAIL / I3C / TPA / p15 / ルテオリン / gadd45 / ゲニステイン / ケルセチン / p53 / RB / p21 / WAF1 |
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| Research Abstract |
Butyrate, a short chain fatty acid, represents one class of histone deacetylase(HDAC) inhibitors, and is an important molecule for preventing colorectal cancer. It is one of the most abundant short chain fatty acids found in the large intestine and is generated by bacterial fermentation of dietary fibers. We discovered that the HDAC inhibitors butyrate and trichostatin A(TSA) inhibit cellular proliferation and induce the expressions of p18^<INK4C> and p19^<INK4d> genes in p16^<INK4a>-deleted human T cell leukemia cell line Jurkat. Furthermore, we demonstrated that the HDAC inhibitors up-regulate the expression of death receptor 5(DR5), a receptor for tumor necrosis factor-related apoptosis-inducing ligand(TRAIL). HDAC inhibitors strongly sensitized exogenous soluble recombinant human TRAIL-induced apoptosis.
Indole-3-carbinol (I3C) is a naturally occurring compound found in vegetables such as broccoli and cauliflower, and has been shown to arrest human tumor cells in the G1 phase of the
… More
cell cycle. However, the molecular mechanism responsible for this effect has not been sufficiently elucidated. We found that I3C activates the cyclin-dependent kinase(CDK) inhibitor p15^<INK4b> gene through its promoter, accompanied by cell growth inhibition in HaCaT cells. Treatment with I3C almost did not affect the expressions of the other CDK inhibitors such as p19^<INK4d>, p21^<WAF1> and p27^<Kip1>. These results suggest that p15^<INK4b> is an important molecular target of I3C among CDK inhibitors.
p18^<INK4c> is a haploinsufficient tumor suppressor. We showed that 12-O-tetradecanoylphorbol-13-acetate(TPA), a tumor promoter, suppresses the expression of p18^<INK4c> through its promoter, accompanied by the induction of cell growth. Reduction of p18^<INK4c> using small interfering RNA also enhanced cell growth, implicating p18^<INK4c> as a critical target of TPA. Protein kinase C inhibitor and curcumin, an anti-tumor promoting agent, abrogated the effect of TPA on p18^<INK4c>. However, dominant negative c-Jun (TAM-67) did not inhibit it. These results suggest the possibility that a mouse two-stage carcinogenesis model using TPA might partially represent human carcinogenesis pathway related to RB. Less
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