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Jeffrey A Winkles
Ph.D.
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| Academic Title:
Professor |
| Primary Appointment:
Surgery |
| Secondary Appointments:
Physiology |
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jwinkles@som.umaryland.edu |
| Location:
800 West Baltimore St.
Biopark Building 1, #320 |
| Phone:
410-706-8172 |
| Fax:
410-706-8234 |
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Personal History
Undergraduate Degree: B.A., Biology, University of Delaware
Graduate Degree: Ph.D., Biology, University of Virginia
Fellowship: National Institutes of Health
Research Interests
The major project in my laboratory is focused on elucidating the biological properties of TWEAK, a member of the TNF superfamily of structurally-related proteins that generally function as either apoptosis factors, immune system regulators, or pro-inflammatory cytokines. TWEAK is a multifunctional protein that can promote cell proliferation, migration, differentiation and pro-inflammatory molecule expression in vitro. It can also stimulate new blood vessel formation (angiogenesis) in vivo. TWEAK induces cellular responses via binding to a relatively small cell surface receptor named Fn14, a protein initially discovered in this laboratory by differential display cloning. TWEAK binding to this receptor activates the NF-kappaB, ERK and JNK signal transduction pathways. Our present research efforts can be categorized as follows:
a. Basic biology and structure/function analysis of the TWEAK-Fn14 system
b. Role of TWEAK in inflammation and angiogenesis
c. Role of the TWEAK-Fn14 system in tumor cell biology
Publications
Selected Publications
Brown, S.A.N., Richards, C.M., Hanscom, H.N., Feng, S.Y. and Winkles, J.A. (2003). The Fn14 cytoplasmic tail binds tumor necrosis factor receptor-associated factors 1, 2, 3 and 5 and mediates NF-kappaB activation. Biochem. J. 371:395-403.
Donohue, P.J., Richards, C.M., Brown, S.A.N., Hanscom, H.N., Buschman, J., Thangada, S., Hla, T., Williams, M.S. and Winkles, J.A. (2003). TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity. Arterioscler. Thromb. Vasc. Biol. 23:594-600.
Ho, D.H., Vu, H., Brown, S.A.N., Donohue, P.J., Hanscom, H.N. and Winkles, J.A. (2004). Soluble TWEAK overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice. Cancer Res. 64:8968-8972.
Brown, S.A.N., Hanscom, H.N., Vu, H., Brew, S.A. and Winkles, J.A. (2006). TWEAK binding to the Fn14 cysteine-rich domain depends on charged residues located in both the A1 and D2 modules. Biochem. J. 397:297-304.
Tran, N.L., McDonough, W.S., Savitch, B.A., Fortin, S.P., Winkles, J.A., Symons, M., Nakada, M., Cunliffe, H.E., Hostetter, G., Hoelzinger, D.B., Rennert, J.L., Michaelson, J.S., Burkly, L.C., Lipinski, C.A., Loftus, J.C., Mariani, L. and Berens, M.E. (2006). Increased Fn14 expression levels promote glioma cell invasion via Rac1 and NF-kappaB and correlate with poor patient outcome. Cancer Res. 66:9535-9542.
Willis, A.L., Tran, N.L., Chatigny, J.M., Charlton, N., Vu, H., Brown, S.A.N., Black, M.A., McDonough, W.S., Fortin, S.P., Niska, J.R., Winkles, J.A. and Cunliffe, H.E. (2008). The Fn14 receptor is highly expressed in HER2-positive breast tumors and regulates breast cancer cell invasive capacity. Mol. Cancer Res. 6:725-734.
Winkles, J.A. (2008). The TWEAK-Fn14 cytokine-receptor axis: Discovery, biology, and therapeutic targeting. Nature Reviews Drug Discovery 7:411-425.
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