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David J Weber
 

David J Weber Ph.D.

Academic Title: Professor
Primary Appointment: Biochemistry and Molecular Biology
Secondary Appointments: Medicine
dweber@umaryland.edu
Location: 108 N. Greene Street, 439
Phone: (410) 706-4354
Phone: (410) 706-6085 (NMR Center)
Fax: (410) 706-0458
Lab: (410) 706-4353

Personal History:

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

Research Interests:

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, S100, 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.

Lab Techniques and Equipment:

Structural biology (NMR, X-ray), Biochemical, Biophysical, Molecular Biology, Cell Biology, and High-Throughput Screening techniques are used in the Weber Laboratory.


Laboratory Personnel:

Current Personnel:

  • Kristen Varney, PhD (Manager of NMR facility)
  • Paul Wilder, PhD
  • Jing Lin
  • Riquing Yang
  • Nathan Wright
  • Thomas Charpentier

Former Students and Post Docs:

  • Dr. Joseph Markowitz
  • Dr. Kristen Varney
  • Dr. Keith Inman
  • Dr. Karen Ellis
  • Dr. Richard Rustandi
  • Dr. Todd Tenenholz
  • Dr. Alex Drohat
  • Dr. Judy Amburgey

Grants and Contracts:

National Institutes of Health (R01 GM58888-11)
PI: David J. Weber
"The structure and function of S100 proteins"

National Institutes of Health (R01 GM58888-S1)
PI: David J. Weber( NIGMS Administrative Supplements for Collaborative Science - competitive grant)
"S100A1 augments CaV1 channel currents and action potential duration in sympathetic ganglion neurons via interaction with protein kinase A (PKA)"

National Institutes of Health (R01 CA107331-04)
PI: David J. Weber
"Restoration of p53 function in malignant melanoma"

National Institutes of Health (R01 CA107331-04-S1)
PI: David J. Weber (ARRA Competitive Revision application)
"Restoration of p53 function in malignant melanoma"

National Institutes of Health (R21CA135624)
PI: Edward Sausville
"Treatment of melanoma with wild-type p53 and detectable S100B using pentamidine:a Phase II trial with correlative biomarker endpoints"

National Institutes of Health (R01 CA124486)
PI: William F. Morgan
High Throughput Screens of Novel Radiation Sensitizers and Protectors


Publications:

Selected Recent Publications

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.

Hernandez-Ochoa, E., Prosser, B.L., Wright, N.T., Contreras, M., Weber, D.J., and Schneider, M.F. Augmentation of Cav1 channel current and action potential duration after uptake of S100A1 in sympathetic ganglion neurons (2009) Am J of Physiol Cell Physiol. In press.

Prosser, B.L., Wright, N.T., Hernandez-Ochoa, E., Varney, K.M., Liu, Y., Olojo, R.O., Zimmer, D.B., Weber, D.J., and Schneider, M.F. S100A1 binds to the calmodulin binding site of RyR1 and modulates skeletal muscle excitation-contraction coupling (2008) J. Biol. Chem., 283, 5046-5057. (Published before April 7, 2008; no PCMIDID).

Wright, N.T., Prosser, B.L., Varney, K.M., Zimmer, D.B., Schneider, M.F., and Weber, D.J. S100A1 and calmodulin compete for the same binding site on the ryanodine receptor (2008) J. Biol. Chem.. 283, 26676-26683. (PCMID:PMC2546546)

Wright, N.T., Inman, K.G., Levine, J.A., Cannon, B.R., Varney, K.M., and Weber, D.J. Refinement and dynamic properties of rat Ca2+-S100B (2008) J. Biomol. NMR., 42, 279-286. (NIHMSID:NIHMS6221) 

Charpentier, T.H., Wilder, P.T., Liriano, M., Varney, K.M., Pozharski, E., MacKerell, A.D., Coop, A., Toth, E.A., and Weber, D.J. Divalent metal ion complexes of S100B in the absence and presence of pentamidine (2008) J. Mol. Biol. 382, 56-73. (PMCID: PMC2636698)

Malashkevich, V., Varney, K.M., Garrett, G.C., Wilder, P.T., Knight, D., Charpentier, T.H., Ramagopal, U.A., Almo, S.C., Weber, D.J., and Bresnick, A.R. Structure of Ca2+-bound S100A4 and its interaction with peptides derived from nonmuscle myosin IIA (2008) Biochemistry, 47, 5111-5126. (PMCID: PMC2633413)

Rifat, D., Wright, N.T., Varney, K.M., Weber, D.J., and Black, L.W. Restriction endonuclease inhibitor IPI* of bacteriophage T4: a novel structure for a dedicated target (2008) J. Mol. Biol. 375, 720-734. (PMCID: PMC2255585)

Markowitz, J., MacKerell, A.D. and Weber, D.J. A search for inhibitors of S100B, a member of the S100 family of calcium-binding proteins (2007) Rev. Med. Chem. 7, 609-616.

Velarde, J., Varney, K.M., Inman, K.G., Farfan, M., Dudley, E., Fletcher, J., Weber, D.J., and Nataro, J.P. Solution structure of the unique dispersin protein of enteroaggregative E. Coli (2007) Mol. Microbiol., 66, 1123-1135.

Blaustein, M.P., Charpentier, T.H., Weber, D.J. Getting a grip on calcium regulation (2007), Proc. Nat. Acad. Sci., 104, 18349-18350.

Wilder, P.T., Charpentier, T.H., and Weber, D.J. Hydrocarbon-stapled helices: A novel approach for blocking protein-protein interactions (2007) Chem. Med. Chem. 2, 1149-1151.