| Project/Area Number |
10044216
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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 |
Applied molecular and cellular biology
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| Research Institution | Nihon University |
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Principal Investigator |
SEKI Taiichiro Nihon University College of Bioresource Sciences, Associate Professor, 生物資源科学部, 助教授 (20187834)
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| Co-Investigator(Kenkyū-buntansha) |
UNO Shigeyuki Nihon University School of Medicine, Assistant Professor, 医学部, 助手 (90307851)
ARIGA Toyohiko Nihon University College of Bioresource Sciences, Professor, 生物資源科学部, 教授 (50096757)
DECLERCK Pau ルーベンカソリック大学, 薬学部, 教授
BRUZDZINSKI キャロリン イリノイ大学, 歯学部, 講師
GELEHRTER Th ミシガン大学, 医学部, 主任教授
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥8,200,000 (Direct Cost: ¥8,200,000)
Fiscal Year 2000: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | PAI-1 / liver / hepatocyte / TGFβ / plasminogen activator |
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| Research Abstract |
Plasminogen activators (PAs) are serine proteases that convert the zymogen plasminogen to the active protease, plasmin. The PA-plasmin cascade plays a central role in processes involving limited protein breakdown, including dissolving blood clots, tissue remodeling, and tumor cell invasion. Type-1 PA-inhibitor (PAI-1) is the major physiologic regulator of plasminogen activation and its expression is tightly regulated. In this project, we have studied the regulation of PA-plasmin system in terms of the molecular mechanisms by which hormones and growth factors regulate expression of the PAI-1 gene. The major results obtained by this project are as follows ; 1) IL-1β is a critical inducer of hepatic PAI-1 gene expression during the acute phase response. Hepatocytes are responsible for the hepatic expression of the PAI-1 gene. 2) Urokinase (uPA) is one of the markers for the differentiation of preadipocytes. Insulin, and dexamethasone are potent regulators of the fibrinolytic activity in differentiated adipocytes, reciprocally affecting PA and PAI-1 levels in them. 3) A novel TGFβ-responsive element was identified in the human PAI-1 gene that is required for mediating transcriptional activation by TGFβ, and that directly binds Smad3 and Smad4, the downstream transducers of TGFβ signaling. 4) A region of the PAI-1 mRNA that confers cyclic nucleotide regulation of mRNA stability was defined. PAI-1 mRNA-binding protein (PAI-RBP1) that identifies a highly conserved family of putative RNA-binding proteins was also isolated and cloned.
These studies will increase our understanding of the molecular mechanisms of gene regulation in the PA-plasmin cascade.
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