Weber, David J. - University of Maryland-Baltimore - Department of Biochemistry and Molecular Biology

个人简介

1993 - present: Promoted through the academic ranks at the University of Maryland School of Medicine. Granted tenure in 1999 and promoted to Full Professor in 2004. 1988-1992: Post Doctoral Fellow, The Johns Hopkins University School of Medicine Department of Biological Chemistry, Advisor: Dr. Albert S. Mildvan 1984-1988: Ph.D., University of North Carolina, Chapel Hill, NC Department of Chemistry, Advisor: Dr. Richard G. Hiskey; Dissertation: "Investigation of Gla-domain Peptides of Prothrombin Binding to Synthetic Phospholipid Membranes" 1980-1984: B.S., Chemistry, Muhlenberg College, Allentown, PA

研究领域

The major project in my laboratory involves studying the structure and function of S100B, a growth factor in the brain and skin. S100B is a dimeric Calcium-binding protein that is overproduced during gliosis in patients with Alzheimer disease, Down syndrome, and Aids related dementia. In addition, S100B and/or other members of the S100 protein family (mts1, S100ï¡, S100L, etc.) are found at high concentrations in several tumor cell lines including skin, lung, bladder, kidney, cervix, breast, head and neck, larynx, lymph, and mouth. Thus, overproduction of S100 proteins may cause problems in the regulation of cell growth in these diseases. Presumably, the function of S100B is related to its ability to bind a variety of target proteins in a Ca2+-dependent manner. One such target is the tumor suppressor protein, p53. For this protein, we have shown that up-regulation of S100B abrogates p53 transcription activation and apoptosis in tumor cell lines and that S100B binds and inhibits both the protein kinase C-dependent phosphorylation and the oligomerization of p53. Therefore, the focus of our laboratory is to determine, at atomic resolution, the mechanism by which S100B can affect p53 transcription activation and promote uncontrolled cell growth. In this regard, we have determined the three-dimensional structure of apo-S100B and the S100B-Ca2+ complex using NMR spectroscopy, and the structure of the S100B-Ca2+-p53 peptide complex is also complete. The structural studies of S100B are imperative for the efficient design of biochemistry and the molecular biology experiments that are also done in our laboratory. Knowledge about the structure and function of S100B are now used to design molecules that inhibit S100B from binding to p53. Patent applications are under review for several of these molecules, and perhaps one or more of these molecules will be practical as a drug for regulating uncontrolled cell growth in vivo. Similarly, structure/function studies are underway for several other members of the S100 protein family including S100A1,mts1 (S100A4), S100A2, S100A3, and others.

近期论文

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House, R. P., Pozzuto, M., Patel, P., Dulyaninova, N. G., Li, Z. H., Zencheck, W. D., Vitolo, M. I., Weber, D. J., and Bresnick, A. R. Two Functional S100A4 Monomers Are Necessary for Regulating NonmuscleMyosin-IIA and HCT116 Cell Invasion (2011) Biochemistry, 50, 6920-6932. Yamaguchi, N., Prosser, B.L., Ghassemi, F., Xu, L., Pasek, D.A., Eu, J.P., Hernández-Ochoa, E.O., Cannon, B.R., Wilder, P.T., Lovering, R.M., Weber, D.J., Melzer, W., Schneider, M.F., and Meissner, G. Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1 (2011) Am. J. Physiol. Cell, 300, 998-1012. PMC Journal - In Process. Malashkevich, V., Dulyaninova, N.G., Liriano, M.A., Varney, K.M., Knight, D., Brenowitz, M., Weber, D.J., Almo, S.C., and Bresnick, A.R. Unique mechanism of S100A4 inhibition: Trifluoperazine- induced protein oligomerization (2010) Proc. Nat. Acad. Sci., 107, 8605-8610. PMC Journal - In Process. Lin, J., Yang, Q., Wilder, P.T., Carrier, F., and Weber, D.J. The calcium-binding protein S100B down- regulates p53 and apoptosis in malignant melanoma (2010) J. Biol. Chem., 285, 27487-27498. PMC Journal - In Process Wilder, P.T., Charpentier, T.H., Liriano, M.A., Gianni, K., Varney, K.M., Pozharski, E., Coop, A., Toth, E.A., MacKerell, A.D. and Weber, D.J.In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction (2010) Int. J. High-Throughput Screening, 1, 109-126.NIHMSID:NIHMS199963. Smith, J., Steward, B.J., Glaysher, S., Peregrin, K., Knight, L.A., Weber, D.J., and Cree, I.A. The effects of pentamidine on melanoma ex vivo (2010) Anti-Cancer Drugs, 21, 181-185.PMCID: PMC2866106. Zimmer, D.Z. and Weber, D.J. The calcium-dependent interaction of S100B with its protein targets (2010) Cardiovasc. Psych. and Neurol., 2010, 1-17. Charpentier, T.H., Thompson, L.E., Liriano, M.A., Varney, K.M., Wilder, P.T., Pozharski, E., Toth, E.A., and Weber, D.J. The effect of the CapZ peptide (TRTK-12) binding to Ca2+-S100B as examined by NMR and X-ray crystallography (2010) J. Mol. Biol., 396, 1227-1243. NIHMSID:NIHMS177816. PMCID: PMC2843395. Malashkevich, V., Dulyaninova, N.G., Liriano, M.A., Varney, K.M., Knight, D., Brenowitz, M., Weber, D.J., Almo, S.C., and Bresnick, A.R. Unique mechanism of S100A4 inhibition: Trifluoperazine-induced protein oligomerization (2010) Proc. Nat. Acad. Sci., 107, 8605-8610. PMC Journal - In Process. Gilquin, B., Cannon, B.R., Hubstenberger, A., Moulouel, B., Falk, E., Merle, N., Assard, N., Kieffer, S., Rousseau, D., Wilder, P.T., Weber, D.J., Baudier, J. The calcium-dependent interaction between S100B and the mitochondrial 1 AAA-ATPase 2 ATAD3A and the role of this complex in the cytoplasmic processing of ATAD3A (2010), Mol. Cell Biol., 30, 2724-2736. PMC Journal - In Process. Weiss, M.B., Vitolo, M.I., Mohseni, M., Rosen, D.M., Denmeade, S.R., Park, B.H., Weber, D.J., and Bachman, K.E. Somatic cell knockout of p53 in human mammary epithelial cells causes chromosomal instability (2010) Oncogene, 29, 4715-4724. PMC Journal - In Process. Lin, J., Yang, Q., Wilder, P.T., Carrier, F., and Weber, D.J. The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma (2010) J. Biol. Chem., 285, 27487-27498. PMC Journal - In Process. Wilder, P.T., Charpentier, T.H., Liriano, M.A., Gianni, K., Varney, K.M., Pozharski, E., Coop, A., Toth, E.A., MacKerell, A.D. and Weber, D.J. In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction (2010) Int. J. High-Throughput Screening, 1, 109-126. NIHMSID:NIHMS199963. Zimmer, D.Z. and Weber, D.J. The calcium-dependent interaction of S100B with its protein targets (2010) Cardiovasc. Psych. and Neurol., 2010, 1-17. Smith, J., Steward, B.J., Glaysher, S., Peregrin, K., Knight, L.A., Weber, D.J., and Cree, I.A. The effects of pentamidine on melanoma ex vivo (2010) Anti-Cancer Drugs, 21, 181-185. NIHMSID:NIHMS189914. Wright, N.T., Cannon, B.R., Wilder, P.T., Morgan, M.T., Varney, K.M., Zimmer, D.B., and Weber, D.J. Solution structure of S100A1 bound to the CapZ peptide TRTK-12 (2009) J. Mol. Biol., 386, 1265-1277. (NIHMSID:NIHMS120897) Charpentier, T.H., Wilder, P.T., Liriano, M.A., Varney, K.M., Zhong, S., Coop, A., Pozharski, E., MacKerell, A.D., Toth, E.A., and Weber, D.J. Small molecules bound to unique sites in the target protein binding cleft of calcium-bound S100B as characterized by nuclear magnetic resonance (NMR) and X-ray crystallography (2009) Biochemistry, 48, 6202-6212. Vitolo, M.I., Weiss, M.B., Szmacinski, M., Tahir, K., Waldman, T., Park, B.H., Martin, S.S., Weber, D.J., and Bachman, K.E. Deletion of PTEN promotes tumorigenic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in human mammary epithelial cells (2009) Cancer Res., in press. Wright, N.T., Cannon, B.R., Zimmer, D., and Weber, D.J. S100A1: Structure, function, and therapeutic potential (2009) Curr. Chem. Biol., 3, 138-145. (NIHMSID:NIHMS121910) Matthews, M.M., Weber, D.J., Shapiro, P.S., Coop, A., and MacKerell, Jr., A.D. Inhibition of protein-protein interactions with low molecular weight compounds (2009) Curr. Trends Med. Chem., in press.