Abstract

Extracellular matrix (ECM) is a complex mixture of proteoglycans that function in cell adhesion, migration, growth and differentiation. In addition, the ECM serves as a reservoir for a number of growth factors, proteinases and proteinase inhibitors essential for ECM homeostasis. Our studies have shown that one of the serine proteinase inhibitors found in the ECM is a 32 kDa glycoprotein consisting of three tandemly- arranged Kunitz-type proteinase inhibitor domains homologous to tissue factor pathway inhibitor, an important negative regulator of blood coagulation. This novel inhibitor, designated as type-2 tissue factor pathway inhibitor, or TFPI-2, in synthesized and secreted into the ECM by endothelial cells, smooth muscle cells, fibroblasts, keratinocytes and urothelium. TFPI-2 readily inhibits several serine proteinase in vitro, strongly inhibited the trypsin or plasmin-mediated activation of promatrix metalloproteinases, and suppressed production of active MMP-2 in tumor cells transfected with the TFPI-2 expression vector. In addition, TFPI-2 expression is up regulated in human atherosclerotic coronary arteries, and its expression in solid tumors inversely correlates with the degree of malignancy. Thus, ECM-associated TFPI-2 may play a pivotal role in the regulation of ECM remodeling, a process essential for angiogenesis, atherogenesis and tumor invasion. The purpose of the studies proposed in this application is to examine in greater detail structure-function relationships in TFPI-2, its inhibitory properties in association with ECM structural proteins, and its role in tumor growth, vascularization and metastasis. Our preliminary data also show that TFPI-2 inhibits mononuclear cell transepithelial migration into airways in a murine model of allergic asthma, and studies are proposed to investigate its mechanism of action in this setting. The long range objectives of this proposal are to accomplish a comprehensive characterization of TFPI-2 in order to delineate its biological role in normal and pathological ECM turnover.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064119-06
Application #
6897301
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
1999-12-01
Project End
2009-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
6
Fiscal Year
2005
Total Cost
$262,500
Indirect Cost

  Institution

Name
University of New Mexico
Department
Pathology
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131

  Publications

Kempaiah, Prakasha; Danielson, Leslie A; Barry, Marc et al. (2009) Comparative effects of aprotinin and human recombinant R24K KD1 on temporal renal function in Long-Evans rats. J Pharmacol Exp Ther 331:940-5
Kempaiah, Prakasha; Chand, Hitendra S; Kisiel, Walter (2009) Human tissue factor pathway inhibitor-2 is internalized by cells and translocated to the nucleus by the importin system. Arch Biochem Biophys 482:58-65
Kempaiah, Prakasha; Kisiel, Walter (2008) Human tissue factor pathway inhibitor-2 induces caspase-mediated apoptosis in a human fibrosarcoma cell line. Apoptosis 13:702-15
Shoji, Mamoru; Sun, Aiming; Kisiel, Walter et al. (2008) Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa. J Drug Target 16:185-97
Sierko, Ewa; Wojtukiewicz, Marek Z; Kisiel, Walter (2007) The role of tissue factor pathway inhibitor-2 in cancer biology. Semin Thromb Hemost 33:653-9
Wojtukiewicz, Marek Z; Sierko, Ewa; Kisiel, Walter (2007) The role of hemostatic system inhibitors in malignancy. Semin Thromb Hemost 33:621-42
Chand, H S; Kisiel, W (2007) Quantitative real-time reverse transcription polymerase chain reaction analysis of a novel tissue factor splice variant in select human solid tumors. J Thromb Haemost 5:640-1
Kempaiah, Prakasha; Chand, Hitendra S; Kisiel, Walter (2007) Identification of a human TFPI-2 splice variant that is upregulated in human tumor tissues. Mol Cancer 6:20
Chand, Hitendra S; Ness, Scott A; Kisiel, Walter (2006) Identification of a novel human tissue factor splice variant that is upregulated in tumor cells. Int J Cancer 118:1713-20
Xu, Zhenhua; Maiti, Debasish; Kisiel, Walter et al. (2006) Tissue factor pathway inhibitor-2 is upregulated by vascular endothelial growth factor and suppresses growth factor-induced proliferation of endothelial cells. Arterioscler Thromb Vasc Biol 26:2819-25

Showing the most recent 10 out of 21 publications