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Jonathan M. Horowitz, Ph.D.

Jon Horowitz

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) Nkx3.1: Nkx3.1 is a homeodomain-containing transcription factor that plays a key role in the formation of the human and mouse prostate gland. Loss of Nkx3.1, due to mutation or deletion, is also associated with prostate tumorigenesis. In recent years we have shown that Nkx3.1 physically interacts with Sp-family members and negatively regulates their capacity to stimulate transcription. Our current efforts are geared towards revealing the precise mechanism whereby Nkx3.1 blocks Sp protein function as well as defining post-translational mechanisms that govern Nkx3.1 function.

(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:

Sterner, J.M., Tao Y., Kennett, S.B., Kim, H.G., Horowitz, J.M. The amino-terminus of the retinoblastoma (Rb) protein associates with a cdk-like kinase via Rb amino acids required for growth suppression. Cell Growth Differ. 7:53-64, 1996.

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.

Baek, S.J., Horowitz, J.M., and Eling, T.E. Molecular cloning and characterization of human NSAID activated gene, NAG-1, promoter: Basal transcription is mediated by Sp1 and Sp3. J. Biol. Chem. 276: 33384-33392, 2001.

Kennett, S.B., Moorefield, K.S., and Horowitz, J.M. Sp3 represses gene expression via the titration of promoter-specific transcription factors. J. Biol. Chem. 277: 9780-9789, 2002.

Moorefield, K.S., Fry, S.J. and Horowitz, J.M. Sp2 DNA-binding activity and trans-activation are negatively regulated in mammalian cells. J. Biol. Chem. 279: 13911-13924, 2004.

Spengler, M.L., Kennett, S.B., Moorefield, K.S., Simmons, S.O., Brattain, M.G., and Horowitz, J.M. Sumoylation of internally-initiated Sp3 isoforms regulates transcriptional repression via a Trichostatin A-insensitive mechanism. Cell. Signal. 17:153-166, 2005.

Simmons, S.O. and Horowitz, J.M. Nkx3.1 negatively regulates a subset of Sp-family members in prostatic epithelia. Biochem.J. 393:397-409, 2006

Moorefield, K.S., Yin, H., Nichols, T.D., Cathcart, C., Simmons, S.O. and Horowitz, J.M. Sp2 localizes to sub-nuclear foci associated with the nuclear matrix. Mol. Biol. Cell 17:1711-1722, 2006.

Rong, Y., Hu, F., Huang, R.P., Mackman, N., Horowitz, J.M., Jensen, R.L., Durden, D.L.,Van Meir, E.G., Brat, D.J. Egr-1 regulates hypoxia-induced expression of tissue factor in glioblastoma through HIF-1 independent mechanisms. Cancer Res. 66: in press, 2006.

Yin, H., Nichols, T.D., Horowitz, J.M. 2010. Transcription of mouse Sp2 yields alternatively spliced and sub-genomic mRNAs in a tissue- and cell type-specific fashion. Biochem Biophys Acta - Gene Regulatory Mechanisms, PMID: 20353838

Lab Personnel


Tamiko Calabrese, Research & Laboratory Support
tjcalabr@unity.ncsu.edu

Tojan Rahhal, Biomedical Engineering Student
tbrahhal@ncsu.edu