| Project/Area Number |
13670493
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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 |
Gastroenterology
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| Research Institution | Showa University |
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Principal Investigator |
YASUDA Hiroshi Showa University, M.D., Associate Professor, 医学部, 講師 (80262129)
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| Co-Investigator(Kenkyū-buntansha) |
IIRI Taroh Univ. of Tokyo School of Medicine, M.D., Assit.Prof., 医学部, 助手 (90313022)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000)
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| Keywords | liver regeneration / Smad / activin / norepinephrine / アクチビン / PKC / Smad |
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| Research Abstract |
Activin A induces growth arrest of rat hepatocytes in vitro and in vivo. The α_1-adrenergic agonist, norepinephrine (NE), enhances epidermal growth factor (EGF)-stimulated DNA synthesis and inhibits activin A-induced growth inhibition, but the mechanisms of these actions are unclear. Smad proteins have recently been identified as intracellular signaling mediators of transforming growth factor (TGF) -β family members. In the present study, we explored how NE modulates the Smad signaling pathway in rat cultured hepatocytes. We demonstrate that NE inhibits activin A-induced nuclear accumulation of Smad2/3, and that NE rapidly induces inhibitory Smad7 mRNA expression. Infection of Smad7 adenovirus into rat hepatocytes inhibited activin A-induced nuclear accumulation of Smad2/3, enhanced EGF-stimulated DNA synthesis and abolished the growth inhibitory effect of activin A. We also demonstrated that the induction of Smad7 by NE is dependent on nuclear factor-KB (NF-KB). The amount of active NF-KB complex rapidly increased after NE treatment. Preincubation of the cells with an NF-KB pathway inhibitor N-tosyl-L-phenylalanine chloromethyl ketone abolished the NE-induced Smad7 expression. These results indicate a mechanism of transmodulation between the Smad and trimeric G protein signaling pathways in rat hepatocytes.
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