2000 Fiscal Year Final Research Report Summary
Regulation of the PA-plasmin cascade
| 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)
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| Project Period (FY) |
1998 – 2000
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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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