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Regulation of urokinase plasminogen ...

McEachron, Troy Anthony.

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Regulation of urokinase plasminogen activator and plasminogen activator inhibitor-1 in murine breast cancer cells.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Regulation of urokinase plasminogen activator and plasminogen activator inhibitor-1 in murine breast cancer cells./
Author:	McEachron, Troy Anthony.
Description:	140 p.
Notes:	Source: Dissertation Abstracts International, Volume: 72-08, Section: B, page: .
Contained By:	Dissertation Abstracts International72-08B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3456287
ISBN:	9781124656304

Regulation of urokinase plasminogen activator and plasminogen activator inhibitor-1 in murine breast cancer cells.
McEachron, Troy Anthony.

Regulation of urokinase plasminogen activator and plasminogen activator inhibitor-1 in murine breast cancer cells. - 140 p.

Source: Dissertation Abstracts International, Volume: 72-08, Section: B, page: .

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2011.

Proteases are indispensable for tumor growth, angiogenesis, and metastasis. These proteases are produced by tumor cells, stromal cells, and by the host coagulation cascade. Protease-activated receptor-1 (PAR-1) and PAR-2 are G protein-coupled receptors that serve as the cellular receptors for several of these proteases, including activated coagulation factor VII (FVIIa), activated coagulation factor X (FXa), and thrombin. PAR-1 and PAR-2 have been found to be overexpressed in breast cancer and activation of these receptors contributes to the malignant phenotype of the cells. Activation of PAR-1 or PAR-2 by coagulation proteases increases the expression of urokinase plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1). uPA and PAI-1 are overexpressed in breast cancer patients and contribute to tumor angiogenesis, tumor growth, and metastasis. Using the highly metastatic 4T1 murine mammary adenocarcinoma model, I examined the effects of coagulation protease-mediated activation of PAR-1 and PAR-2 on the plasminogen activator system. Specifically, I focused my studies on how activation of PAR-1 and PAR-2 by FXa and thrombin regulate uPA and PAI-1 expression in 4T1 cells.

ISBN: 9781124656304Subjects--Topical Terms:

1017719
Biology, Molecular.

Regulation of urokinase plasminogen activator and plasminogen activator inhibitor-1 in murine breast cancer cells.
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020 $a 9781124656304
035 $a (UMI)AAI3456287
035 $a AAI3456287
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100 1 $a McEachron, Troy Anthony. $3 1684944
245 1 0 $a Regulation of urokinase plasminogen activator and plasminogen activator inhibitor-1 in murine breast cancer cells.
300 $a 140 p.
500 $a Source: Dissertation Abstracts International, Volume: 72-08, Section: B, page: .
500 $a Advisers: Frank C. Church; Nigel Mackman.
502 $a Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2011.
520 $a Proteases are indispensable for tumor growth, angiogenesis, and metastasis. These proteases are produced by tumor cells, stromal cells, and by the host coagulation cascade. Protease-activated receptor-1 (PAR-1) and PAR-2 are G protein-coupled receptors that serve as the cellular receptors for several of these proteases, including activated coagulation factor VII (FVIIa), activated coagulation factor X (FXa), and thrombin. PAR-1 and PAR-2 have been found to be overexpressed in breast cancer and activation of these receptors contributes to the malignant phenotype of the cells. Activation of PAR-1 or PAR-2 by coagulation proteases increases the expression of urokinase plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1). uPA and PAI-1 are overexpressed in breast cancer patients and contribute to tumor angiogenesis, tumor growth, and metastasis. Using the highly metastatic 4T1 murine mammary adenocarcinoma model, I examined the effects of coagulation protease-mediated activation of PAR-1 and PAR-2 on the plasminogen activator system. Specifically, I focused my studies on how activation of PAR-1 and PAR-2 by FXa and thrombin regulate uPA and PAI-1 expression in 4T1 cells.
520 $a I found that FVIIa does not alter uPA or PAI-1 levels. However, both FXa and thrombin induced uPA release from 4T1 cells in a PAR-1-dependent manner. Further experiments revealed that uPA was not regulated at the transcriptional level but rather secreted upon PAR-1 activation. Surprisingly, thrombin, but not FXa, induced PAI-1 mRNA and protein expression and this required expression of both PAR-1 and PAR-2, indicating receptor cooperation. The intracellular signaling pathway regulating thrombin-induced PAI-1 expression in 4T1 cells was also examined. Stimulating 4T1 cells with thrombin activated the ERK1/2-ELK1-EGR1 pathway. Inhibition of p42/p44 MAPK signaling reduced PAI-1 protein levels, suggesting that this pathway is required for thrombin-induced PAI-1 expression in 4T1 cells. In conclusion, I propose a model in which coagulation proteases activate PAR-1 and PAR-2 on 4T1 cells resulting in uPA secretion and in PAI-1 mRNA and protein expression, thereby contributing to breast tumor progression.
590 $a School code: 0153.
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Pathology. $3 1017854
690 $a 0307
690 $a 0571
710 2 $a The University of North Carolina at Chapel Hill. $b Pathology. $3 1684945
773 0 $t Dissertation Abstracts International $g 72-08B.
790 1 0 $a Church, Frank C., $e advisor
790 1 0 $a Mackman, Nigel, $e advisor
790 1 0 $a Richards, Kristy $e committee member
790 1 0 $a Miller, C. Ryan $e committee member
790 1 0 $a Rak, Janusz $e committee member
790 $a 0153
791 $a Ph.D.
792 $a 2011
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3456287