Shirley Taylor, Ph.D.
Associate Professor, Director Molecular Biology Supply Center, Director Molecular Core Laboratory

Phone: (804) 828-5773
Dept. Fax: (804) 828-5782
e-mail: smtaylor@vcu.edu

Address:
Department of Microbiology & Immunology
Virginia Commonwealth University
Massey Cancer Center Goodwin Research Laboratory Room 112 & Lab 111           P.O. Box 980037
401 College Street
Richmond, VA 23298-0037

Professional Experience

• B.S., 1974, University of Cape Town, South Africa 
• B.S. (Hons), 1976 University of Stellenbosch, South Africa
• M.S., 1977, University of Stellenbosch, South Africa
• Ph.D., 1981, University of Southern California
• Postdoctoral, 1982-86, California Institute of Technology

Research Interests:

DNA methylation, Cell Differentiation and Cancer. The research interests of my laboratory have been centered on the control of DNA methylation and its role in cell differentiation and cancer. In the late 70's, we discovered the powerful effects of the cytidine analogs, 5-aza-cytidine and 5-aza-2'-deoxycytidine on cell differentiation (1,2): these compounds were capable of changing the developmental potential of cultured mouse cells. Fibroblasts transdifferentiated into skeletal muscle, adipocytes and chondrocytes, as a result of the inhibition of DNA methylation by the 5-modified cytidine analogs (3). It is now widely accepted that DNA methylation plays a fundamental role in controlling expression of a wide variety of genes, most likely in concert with changes in chromatin configuration, through the histone acetyltransferases and deacetylases (13). Our current research focuses on the interactions between DNA methyltransferase 1 (DNMT 1) and other proteins that occur during replication, to maintain the state of methylation in the somatic cell genome. We have generated an affinity-tagged allele of DNMT1 by homologous recombination, expressed under its normal control mechanisms and at endogenous levels, so that we might understand these interactions under physiologically relevant conditions. We are applying proteomic approaches with tandem mass spectrometry to understand how these interactions are altered when cells undergo differentiation or oncogenic transformation. We are particularly interested in the relationship between tumor suppressor gene inactivation and DNA methylation during tumor progression, and have focused on the p53 tumor suppressor gene, which is altered in more than 50% of all tumors studied to date. These studies use a transgenic mouse brain tumor model to understand the role of DNA methylation in the initial silencing of the p53 gene and the subsequent loss of the wild type allele during tumor progression. We recently discovered (8) that p53 negatively regulates the expression of DNA methyltransferase 1, the enzyme responsible for maintaining patterns of methylation in the mammalian genome. Loss of this negative regulation, resulting from alterations in p53 function, provides a model for the accumulation of inappropriate methylation events, which lead to tumor progression (10,11).

During 2008, we discovered that the DNA methyltrasferase 1 locus encodes an isoform that directs the enzyme to the mitochondria.  This exciting discovery allows us for the first to begin to understand how mitochondrial DNA methylation is established and maintained, and its role in heart disease and cancer.

Antifolate Drug Discovery

Collaborative projects with Dr. Richard Moran, Department of Pharmacology & Toxicology, VCU are aimed at understanding and defining new targets for folate-based anticancer drug discovery (4,5). The enzyme folylpolyglutamate synthetase is responsible for polyglutamation of folate cofactors as well as analogs that are potential inhibitors of folate dependent enzymes. Molecular analysis of this locus has revealed two isoforms encoded by the same gene with subtle differences in substrate activity and whose expression patterns in mouse and man suggest interesting mechanisms in tissue specific gene control (6,7,13). These expression patterns might permit the structure-based design of new generations of antifolate analogs whose metabolism and activity would be limited to specific tissues and/or tumors. We have uncovered a novel mechanism for resistance to the class of antifolates that are inhibitors of de novo purine synthesis (eg dideazatetrahydrofolate) (6), and have begun to understand the role of mitochondrial metabolism in the activity of this class of drugs (9,12).

Selected Publications:

1. Taylor, S.M. and Jones, P.A. Multiple New Phenotypes Induced in 10T1/2 and 3T3 cells Treated with 5-azacytidine. Cell, 17, 771-779 (1979).

2. Jones, P.A. and Taylor, S.M. : Cellular Differentiation, Cytidine Analogs and DNA Methylation. Cell, 20, 85-93. (1980).

3. Taylor, S.M. and Jones, P.A.: Mechanism of Action of Eukaryotic DNA Methyltransferase: Use of 5-azacytosine Containing DNA. J. Mol. Biol., 162, 679-692. (1982).

4. Freemantle, S.J., Taylor, S.M., Krystal, G. and Moran, R.G. Upstream Organization of and Transcription from the Human Folylpoly- g -glutamate Synthetase Gene. J. Biol. Chem, 270: 9579-9584. (1995).

5. Kan, J.L.C., Jannatipour, M., Taylor, S.M. and Moran, R.G. Mouse cDNAs for a Trifunctional Protein of de novo Purine Synthesis and a Related Single Domain Glycinamide Ribonucleotide Synthetase. Gene, 137: 195-202. (1993).

6. Turner, F.B., Andreassi, J.L. III , Ferguson , J., Titus, S., Tse, A., Taylor , S.M. and Moran, R.G. Tissue-specific Expression of Functional Isoforms of Mouse Folylpoly- g -glutamate Synthetase: a Basis for Targeting Folate Antimetabolites. Cancer Res, 59: 6074-6079 (1999).

7. Turner, F.B., Taylor , S.M. and Moran, R.G. Expression Patterns of the Multiple transcripts from the Folylpolyglutamate Synthetase gene in Human Leukemias and Normal Differentiated Tissue. J. Biol.Chem. 275:35960-35968 (2000).

8. Peterson, E.J., Bogler, O. and Taylor , S.M. p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res, 63:6579-6582 (2003).

9. McCarthy, E., Titus, S., Taylor, S.M. Jackson-Cooke, C. and Moran, R.G. An inactivating mutation in the hamster mitochondrial folate transporter gene explains the glyB phenotype. J. Biol. Chem, 2004, 279: 33829 – 33836.

10. Taylor, S.M. p53 and deregulation of DNA methylation in Cancer. Cell Science Reviews, 2006, 2: 82-93.

11. Arjona, D., Rey, J.A. and Taylor, S.M.. Early genetic changes in low-grade astrocytic tumor development. Curr. Mol. Med., 2006, 6: 645-650.

12. Perchiniak, E., Lawrence, S.A., Kasten, S., Woodard, B.A., Taylor, S.M. and Moran, R.G. Probing the mechanism of the hamster mitochondrial folate transporter by mutagenesis and homology modeling. Biochemistry, 2007, 46: 1557-1567.

13.  Racanelli, A.R., Turner, F.B., Xie, L.,Taylor, S.M., and Moran, R.G.  Epigenetic mechanisms in the dual promoter system controlling mouse fpgs tissue-specific expression, Mol Cell Biol, 2008, 28: 836-848.

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Date Last Modified: 09/03/2009
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