Horowitz, Jonathan, M., PhD
Associate Professor, College of Veterinary Medicine,
Department of Molecular Biomedical Sciences

Ph.D.: University of Wisconsin
Molecular Biology, 1985
Laboratory of Dr. Rex G. Risser, Ph.D.
Post-doctoral: Fellow, 1986-1989
Massachusetts Institute of Technology
Whitehead Institute for Biomedical Research, Cambridge, MA.
Laboratory of Dr. Robert A. Weinberg, Ph.D

Phone: (919) 515-4479
Fax: (919) 515-3044
E-mail: jon_horowitz@ncsu.edu
Lab page: http://www4.ncsu.edu/~jmhorowi/horowitz_web/horowitzlab.htm


Research Area:

The research in our laboratory is focused on mechanisms of negative-growth regulation, specifically the role of a tumor-suppressor gene product, the retinoblastoma (Rb) protein, in the control of mammalian cell proliferation and differentiation. The Rb protein is believed to function to limit or constrain cell proliferation at least in part by forming cell cycle-regulated protein complexes with a constellation of transcription factors. In recent years our efforts have focused on the following three inter-related areas of research:

(1) Regulation of the Sp-Family of Transcription Factors by Rb: We have shown that trans-activation by two members of the Sp-family of transcription factors, Sp1 and Sp3, is "superactivated" by Rb in vivo. In addition we have shown that Sp3 encodes at least three distinct proteins, two result from internal translational initiation, and internally initiated Sp3 proteins function as potent repressors of Sp1/Sp3-mediated transcription. Current efforts are directed towards understanding the precise mechanisms governing Rb-mediated "superactivation".

(2) Rb-Binding Proteins: We have shown that Rb binds and regulates MCM7, a protein required for the initiation of DNA replication. The amino-termini of Rb and two Rb-related proteins, p107 and p130, bind MCM7 in vitro and in vivo, and Rb and p130 can block DNA replication in vitro in an MCM7-dependent fashion. These results provide the first evidence that DNA replication is directly regulated by tumor-suppressor genes.

(3) Novel Dimerization Partners of E2F/DP Proteins: We have defined a series of preferred DNA-binding sites for a variety of E2F/DP and Rb/E2F/DP complexes. These studies have shown that E2F complexes prefer particular E2F-binding sites, that E2F and DP proteins play a role in the selection of such sites, that Rb significantly alters the DNA-binding site specificity of E2F/DP complexes, and that E2F sites selected in vitro exhibit distinct patterns of cell cycle-regulated transcription in vivo.

Representative Publications:

Rogers, K.T., Higgins, P.D.R., Milla, M., Phillips, R.S., Horowitz, J.M. DP-2, a heterodimeric partner of E2F: Identification and characterization of DP-2 proteins expressed in vivo. Proc. Natl. Acad. Sci. U.S.A. 93:7594-7599, 1996.

Cuevo, R.S., Garrett, S., Horowitz, J.M. Detection and functional characterization of p180, a novel cell-cycle regulated yeast transcription factor that binds retinoblastoma control elements (RCEs). J. Biol. Chem. 272:3813-3822, 1997.

Kennett, S.B., Udvadia, A.J., Horowitz, J.M. Sp3 encodes multiple proteins that differ in their capacity to stimulate or repress transcription. Nucl. Acids Res. 25:3110-3117, 1997.

Tao, Y., Kassatly, R.F., Cress, D., and Horowitz, J.M. Subunit composition determines E2F-binding site specificity. Mol. Cell. Biol. 17:6994-7007, 1997.

Sterner, J.M., Dew-Knight, S., Musahl, C., Kornbluth, S., and Horowitz, J.M. Negative regulation of DNA replication by the retinoblastoma protein is mediated by its association with MCM7. Mol. Cell. Biol. 18:2748-2757, 1998.

Lee, R.J., Albanese, C., Fu, M., D'Amico, M., Lin, B.G., Watanabe, G.K., Haines III, P.M. Siegel, Muller, W.J., Yarden, Y., Horowitz, J.M., Hung, M.-C., and Pestell, R.G. Cyclin D1 is required for transformation and is transcriptionally activated by Neu/erbB-2. Mol. Cell. Biol. 20:672-683, 2000.

Links:

Horowitz Lab Personnel

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