David J. Weber  Ph.D.
Professor
Director, Joint Program in Biochemistry and Molecular Biology
Director, University of Maryland NMR Facility

EDUCATION: 1992 -Post Doctoral Fellow            Johns Hopkins University            School  of Medicine             Department of Biological Chemistry 1988 - Ph.D.            University of North Carolina, Chapel Hill            Department of Chemistry 1984 - B.S., Chemistry,            Muhlenberg College            Allentown, PA                      108 N. Greene Street, Room 439A                     Baltimore, Maryland 21201                     Phone (410) 706-4354                     Fax (410) 706-0458                     Email: dweber@umaryland.edu

Research Interest:
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 Ca²⁺-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, S100a, 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 upregulation 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-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.  Several of these molecules are now patented, and 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, mts1 (S100A4), S100A2, and S100A3.

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Associated sites:
                   
University of Maryland School of Medicine NMR facility   

University of Maryland School of Medicine Graduate Program

Lab Personnel:

Dr. Jing Lin
Dr. Paul Wilder
Thomas Charpentier
Nathan Wright
Ruiqing Yang

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                                                                     

Wilder, P.T., Varney, K.M, Weis, M.B., Gitti, R.K., and Weber, D.J.  Solution structure of zinc and calcium-bound rat S100B as determined by nuclear magnetic resonance spectroscopy (2005) Biochemistry, 44, 5690-5702. (PDB file: 1XYD)  PDF file

Markowitz, J., Rustandi, R.R., Varney, K.M., Wilder, P.M., Udan, R., Wu, S.L., Horrock, W.D., and Weber, D.J. Calcium-binding properties of wild-type and EF-hand mutants of S100B in the presence and absence of a peptide derived from C-terminal negative regulatory domain of p53 (2005) Biochemistry, in press.   PDF file 

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., 279, 34071-34077.  PDF file

Markowitz, J., Chen, I., Gitti, R., Baldisseri, D.M., Pan, Y., Udan, R., Carrier, F., MacKerell, A.D., and Weber, D.J.  Identification and characterization of small molecule inhibitors of the calcium-dependent S100B-p53 tumor suppressor interaction (2004) J. Med. Chem. 47, 5085-5093.   PDF file

Patents:
Weber, D. J., Markowitz, J., Carrier, F., MacKerell, A.D. “Inhibitors of the S100-p53 protein-protein interaction and method of inhibiting cancer employing the same”. U.S. Patent application 10/397,239.

Weber, D.J., Markowitz, J., Carrier, F., MacKerell, A.D. “Identification and characterization of small molecule inhibitors of the calcium-dependent S100B-p53 tumor suppressor interaction”. U.S. Patent application 60/581,018.