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Molecular Medicine


David Loskutoff, Ph.D.

Professor Emeritus
Department of Molecular Medicine
California Campus

Research Focus

Regulation of Cell Mediated Proteolysis by
Type 1 Plasminogen Activator Inhibitor

The activation of plasminogen provides an essential source of localized proteolytic activity for cells during tumor invasion, angiogenesis, cell migration, epithelial differentiation, ovulation, and for a variety of other physiologic events including the removal of pathological blood clots. Precise regulation of plasminogen activator (PA) activity is achieved through the action of type 1 PA inhibitor (PAI-1). PAI-1 itself is produced by a variety of cells and accumulates in their extracellular matrix (ECM) where it is bound to vitronectin (VN). Its synthesis is stimulated by growth factors, cytokines and hormones. Our long-term objective is to define the cellular events that regulate PAI-1 synthesis, secretion, and activity by using biochemical, cellular, and molecular biological approaches to study cultured endothelial cells, murine models of human disease, and human vascular tissue. One current focus of our studies is to define the interaction between PAI-1 and VN, and to delineate how these interactions regulate PAI-1 activity. The mechanisms by which PAI-1 modulates integrin-independent and dependent cell adhesion also are being investigated. A second area of interest involves the mechanisms by which insulin, transforming growth factor, and tumor necrosis factor elevate PAI-1 gene expression both in normal and obese mice, and in various insulin-resistant states. The tissues and cells that produce PAI-1 mRNA and protein in vivo in the obese mouse and in human atherosclerotic tissue are being studied by using competitive PCR assays as well as in situ hybridization analysis. Finally, the contribution of PAI-1, VN and leptin to thrombus formation and dissolution, to vascular remodeling after injury (restenosis), and to angiogenesis, is being investigated in knockout mice lacking specific genes. These studies should lead to a better understanding of PAI-1 and its role in the pathogenesis of human vascular disease.

Awards & Professional Activities

Member International Scientific Review Board, Dipartimento di Ricerca Biologicà e Tecnologica, Università Vita-Salute S. Raffaele, Milan, Italy

Selected References

Kamikubo, Y., De Guzman, R., Kroon, G., Curriden, S., Neels, J.G., Churchill, M.J., Dawson, P., Oldziej, S., Jagielska, A., Scheraga, H.A., Loskutoff, D.J., Dyson, H.J.Disulfide bonding arrangements in active forms of the somatomedin B domain of human vitronectin. Biochemistry, 43:6519-6534, 2004.

Schäfer, K., Halle, M., Goeschen, C., Dellas, C., Pynn, M., Konstantinides, S., Loskutoff, D.J. Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol. 24:112-117, 2004.

Sartipy, P. and Loskutoff, D.J. Expression profiling identifies genes that continue to respond to insulin in adipocytes made insulin-resistant by treatment with tumor necrosis factor-a. J.Biol.Chem. 278:52298-52306, 2003.

Czekay, R.-P., Aertgeerts, K., Curriden, S.A., Loskutoff, D.J. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J.Cell Biol. 160:781-791, 2003.

Molecular Medicine Seminar Series
Center for Physiological Proteomics
Department Contacts

CA Faculty

Asahara, Hiroshi
Balch, William E.
Boddy, Michael
Buxbaum, Joel
Catz, Sergio
Conti, Bruno
Cravatt, Benjamin
D'Lima, Darryl
DerMardirossian, Celine
Deryugina, Elena
Elias, Darlene
Encalada, Sandra
Felding, Brunhilde
Fowler, Velia
Friedlander, Martin
Gerace, Larry
Gottesfeld, Joel
Griffin, John
Hanneken, Anne
Heeb, Mary Jo
Henderson, Scott
Hoch, James
Johnson, Eric
Kanaji, Taisuke
Koziol, James
Lamia, Katja
Lipton, Stuart
Loring, Jeanne F.
Loskutoff, David
Lotz, Martin
Makarenkova, Helen P.
Mc Millan, Robert
Miles, Lindsey
Milner, Richard
Modena, Brian
Mosnier, Laurent
Nicholson, Laura
Paulson, James C.
Perego, Marta
Petrascheck, Michael
Pollard, Kenneth Michael
Quigley, James P.
Reed, Steven
Roberts, Edward
Rosen, Hugh
Ruggeri, Zaverio
Russell, Paul
Saez, Enrique
Smider, Vaughn
Srinivasan, Supriya
Steinhubl, Steven
Sutcliffe, J.
Tan, Eng
Topol, Eric
Vanderklish, Peter
Vogt, Peter K.
Wiseman, Luke
Wittenberg, Curt
Wolan, Dennis W.
Wu, Peng
Wu, Xiaohua
Yang, Xiang-Lei
Yates III, John

FL Faculty

Bannister, Thomas
Bohn, Laura M.
Cameron, Michael
Duckett, Derek
Gill, Matt
Griffin, Patrick
Hansen, Scott
Joazeiro, Claudio
Kamenecka, Theodore
Kissil, Joseph
Luo, Junli
McDonald, Patricia
Miller, Courtney
Niedernhofer, Laura
Phinney, Donald G.
Robbins, Paul
Scampavia, Louis
Schimmel, Paul
Smith, Roy
Spicer, Timothy

Affiliated Faculty

Cline, Hollis
Kojetin, Douglas
Lairson, Luke
Paegel, Brian
Rumbaugh, Gavin
Shen, Ben
Solt, Laura A
Su, Andrew
Wu, Chunlei
Ye, Li

Adjunct Faculty