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Researcher Information

David J. Weber, Ph.D.
Professor of Biochemistry
Director, Center for Biomolecular Therapeutics
Associate Director, Institute for Bioscience and Biotechnology Research

Department:
Biochemistry and Molecular Biology

UMGCC Research Program:
Molecular and Structural Biology Program

Education/Training:
College Degree: B.S. Muhlenberg College
Post Doctoral Degree: Ph.D., University of North Carolina-Chapel Hill; Johns Hopkins University School of Medicine

Contact Information:

Mailing Address: Department of Biochemistry and Molecular Biology
108 N. Greene St.
Baltimore, MD 21201
Email: dweber@umaryland.edu
Phone: 410-706-4354
Fax: 410-706-0458

Research Interests:
The major project in my laboratory involves studying the structure and function of S100B, a glial-derived growth factor in the brain and skin. S100B is a dimeric calcium-binding protein that is overproduced during gliosis in patients with Alzheimer's disease, Down syndrome, and AIDS-related dementia. In addition, S100B and/or other members of the S100 protein family (mts1, S100A1, 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 calcium-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 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-calcium complex using NMR spectroscopy, and the structure of the S100B-calcium-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. Perhaps one of these molecules will be practical as a drug for regulating uncontrolled cell growth in vivo. Similarly, structure/function studies are underway for four other members of the S100 protein family, S100A1, ƒ¡ƒzƒnmts1 (S100A4), S100A2, and S100A3.

Publications:
Lin, J., Yang, Q., Yan, Z., Markowitz, J., Wilder, P.T., Carrier, F., and Weber, D.J. Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells (2004) J. Biol. Chem., in press.

Wilder, P.T., Baldisseri, D.M., Udan, R., Vallely, K.M., and Weber, D.J. Location of the Zn2+ binding site on S100B as determined by NMR spectroscopy and site-directed mutagenesis (2003) Biochemistry, 42, 13410-13421

Vallely, K.M., Rustandi, R.R., Ellis, K.C., Varlamova, O., Bresnick, A.R., and Weber, D.J. Solution structure of human mts1 (S100A4) as determined by NMR spectroscopy (2002) Biochemistry, 41, 12670-12680.

Rustandi, R.R., Baldisseri, D.M. and Weber, D.J. Solution structure of the negative regulatory domain of p53 in a complex with Ca2+-bound S100B (2000) Nature Structural Biology, 7, 570-574.