Research Interests
General Research Statement:
The research area of this laboratory is concerned with proteases and their inhibitors in human biology and in various disease processes (thrombosis and cancer). We investigate this area using different approaches: In one approach, we perform structureactivityfunction studies with Serpins (serine protease inhibitors) and serine proteases. This research is aimed at understanding the molecular mechanism of protein-protein recognition between proteases and inhibitors (and glycosaminoglycans). In another approach, we study the role(s) of proteases in pathological processes by describing the in vivo localization and molecular regulation of proteases and inhibitors in tissues (and tumor cell lines), especially breast and gynecological cancers. Limited-proteolysis is important for normal and abnormal processes and we are dissecting interactions between proteases and their inhibitors that promote thrombosis and tumor cell processes.

Cancer-related Research Statement:
One in nine women will be diagnosed with breast cancer. A significant percentage of women will already have metastatic cancers at the time of diagnosis and even though the 5-year survival rates have improved, a majority of women will still succumb to recurrent disease. To develop metastatic disease, the extracellular matrix surrounding the cancer must be degraded, allowing cancer cells to travel to distant sites. Matrix degradation is mediated by proteases, one of which is urokinase plasminogen activator (uPA). A specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), regulates uPA activity. Surprisingly, an elevated level of PAI-1 is a poor prognostic factor for breast cancer patients. It is unclear why a substance that blocks matrix degradation would be linked to a poor prognosis. Our objective is to understand the "paradox" of why too much PAI-1 is detrimental to women with breast cancer. We believe that expression of PAI-1 confers a survival advantage upon breast cancer cells. Our results will shed valuable information on the role of PAI-1 in one of the most significant problems hindering the treatment of women with breast cancer, invasion and metastasis.

Understanding recurrent disease is one of the most critical areas of ovarian cancer biology and fundamental for the development of effective treatment regimens. The vast majority of women diagnosed with ovarian cancer will experience recurrent disease within 5 years. Treatment options for these patients are often limited. The seeding of metastatic tumor masses throughout the peritoneal cavity marks recurrent ovarian cancer. Metastatic cancers are the result of the migration of cells from the initial tumor mass and occur following both loss of adhesion between cells and the extracellular matrix and significant alterations in the cell architecture. The destruction of adhesive contacts is made in part by members of the plasminogen activator family. Expression of urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) have been shown to be up-regulated in the majority (>50%) of ovarian cancers and are independent poor prognostic factors for patient survival. As with other cancers, uPA expression and activity is believed to be critical for metastasis. We are studying ovarian tumor cells lines and their ability to adhere, migrate and invade in an in vitro environment, and the signaling process that is transmitted by the plasminogen activator system. We are studying by immunohistochemistry, the occurrence of serpins and their proteases in primary and metastatic ovarian cancer. We believe that the results of this work will ultimately benefit women with metastatic, recurrent ovarian cancer.

Publications
1. Patston, P.A., F.C. Church, and S.T. Olson (2003) Serpin-ligand interactions. Methods. In press.
2. Glasscock, L.N., B. Gerlitz, S.T. Cooper, B.W. Grinnell, and F.C. Church (2003) Basic residues in the 37-loop of activated protein C modulate inhibition by protein C inhibitor but not by ?1-antitrypsin Biochimica Biophysica Acta. 1649:106-117.
3. Whitley, B.R., D. Palmieri, C. Twerdi, and F.C. Church (2003) Expression of active plasminogen activator inhibitor-1 regulates cell migration and invasion in breast and gynecological cancer cells. Submitted for publication.
4. Glasscock, L.N., S.M. Rehault, C.W. Gregory, Cooper, S.T., Jackson, T.P., Hoffman, M., and F.C. Church. Evidence for protein C inhibitor/plasminogen activator inhibitor-3 expression in human prostatic carcinoma. Manuscript in preparation.
5. Palmieri, D., J.-W. Lee, R.L. Juliano and F.C. Church (2002) Expression of plasminogen activator inhibitor-type 1 and 3 increase cell adhesion and motility of MDA-MB-435 cancer cells. J. Biol. Chem. 277: 40950-40957.
6. Mitchell, J.W. and F.C. Church (2002) Aspartic acid residues 72 and 75 and tyrosine-sulfate 73 of heparin cofactor II promote intramolecular interactions during glycosaminoglycan binding and thrombin inhibition. J. Biol. Chem. 277: 19823-19830.
7. Baglin, T., R.W. Carrell, F.C. Church, C.T. Esmon and J.A. Huntington (2002) Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism. Proc Natl Acad Sci U S A. 99: 11079-11084.
8. Silverman G.A., P.I. Bird, R.W. Carrell, F.C. Church, P.B. Coughlin, P.G. Gettins, J.A. Irving, D.A. Lomas, C.J. Luke, R.W. Moyer, P.A. Pemberton, E. Remold-O'Donnell, G.S. Salvesen, J. Travis, and J.C. Whisstock (2001) The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J. Biol. Chem. 276: 33293-33296.



Bushman, J.E., D. Palmieri, H.C. Whinna, and F.C. Church (2000) Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia. Leukemia Res. 27 (7): 559-565.

Bauman, S.J. and F.C. Church (1999) Enhancement of heparin cofactor II anticoagulant activity. J. Biol. Chem. 274: 34556-34565.

Shirk, R.A., N. Parthasarathy, J.D. San Antonio, F.C. Church, and W.D. Wagner (2000) Human aortic biglycan and decorin dermatan sulfate proteoglycan from atherosclerotic plaque possess altered structure and reduced activity with heparin cofactor II. J. Biol. Chem. in press, summer 2000

Myles, T., F.C. Church, H.C. Whinna, D. Monard, and S.R. Stone (1998) Role of thrombin anion-binding exosite-I in the formation of thrombin-serpin complexes. J. Biol. Chem. 273: 31203-31208.

Elisen, M.G.L.M., B.N. Bouma, F.C. Church, and J.C.M. Meijers (1998) Inhibition of serine proteases by reactive site mutants of protein C inhibitor. Fibrinol. Proteol. 12: 283-291.

Neese, L.L., C.A. Wolfe, and F.C. Church (1998) Contribution of basic residues of the D and H helices in heparin binding to protein C inhibitor. Arch. Biochem. Biophys. 355: 101-108.

Ciaccia, A.V., D.M. Monroe, and F.C. Church (1997) Arginine 200 of heparin cofactor II promotes intramolecular interactions of the acidic domain: Implications for thrombin inhibition. J. Biol. Chem. 272: 14074-14079.

Jackson, T.P., S.T. Cooper and F.C. Church (1997) Assessment of the interaction between urokinase and reactive site mutants of protein C inhibitor. J. Protein Chem. 16: 819-828.

Ciaccia, A.V., Willemze, A.J., and F.C. Church (1997) Heparin promotes proteolytic inactivation by thrombin of a reactive site mutant (L444R) of recombinant heparin cofactor II. J. Biol. Chem. 272: 888-893.

Church, F.C., D.D. Cunningham, D. Ginsburg, M. Hoffman, D.M. Tollefsen, and S.R. Stone (1997) "Chemistry and Biology of Serpins (Serine Proteinase Inhibitors)". Plenum Press, New York. Adv. Exp. Med. Biol. Vol. 425: 358 pages.

E-mail: fchurch@email.unc.edu
Telephone: (919) 966-3311
FAX: (919) 966-7639
Address: 942 Mary Ellen Jones Building Chapel Hill, NC 27599-7135
URL: http://serpins.med.unc.edu/~fcc

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