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Richard G. Moran, Ph.D. Richard G. Moran, Ph.D.
Professor
401 College Street
Goodwin Cancer Research Facility
P.O. Box 980035
Richmond, Virginia 23298-0035
Phone: (804) 828-5783
E-mail: rmoran@vcu.edu
Publications: selected | PubMed

Education: State University of New York at Buffalo, 1974

Research interests:

Design and Mechanism of Cancer Therapeutic Agents

My laboratory is interested in the biochemical and molecular phenomena underlying the selectivity of anticancer drugs and in design of new agents that take advantage of the loss of function of tumor suppressor gene functions in human cancers. In the past few years, we have been active in three areas:

1. The protein chemistry of mammalian folylpolyglutamate synthetase and molecular controls on the transcription on the fpgs gene. In the past, this interest has led my laboratory into design and development of inhibitors of folate metabolism as cancer drugs that were trapped in tumor cells by virtue of substrate activity for the FPGS reaction. In recent years, this area has led us into dissection of the intriguing set of control mechanisms that determine coordinate transcription from two promoters in the mouse fpgs gene. These control mechanisms include tissue-specific assembly of a pre-initiation complex at a CpG-sparse promoter, tissue-specific DNA methylation over this promoter, epigenetic marking of this promoter by several histone modifications in some tissues coordinate with transcriptional activity. At the other promoter, which contains a CpG island, a PIC is assembled in most tissues, whether or not trancription is initiated at this promoter, and the promoter is subject to promoter interference and occlusion by activity at the upstream promoter.
We are determining the generality of these interacting controls at multi-promoter genes, which amount to > 50% of promoters in the human genome, and are attempting to learn how the control mechanisms change when promoter use is switched from the one promoter to the other.

2. The mechanism of transport of anions through the mitochondrial membrane and the role of this transport in toxicity of the folate antimetabolites. Following the cloning of the gene for the inner mitochondrial membrane folate transporter by a former laboratory member, we have come to appreciate the similarities of this MFT transport to that catalyzed by other members of this gene family, and also the striking differences in the MFT protein. These differences offer an understanding of the details of the mechanism of the transport process, and the biophysics of how the transport channel opens and closes, allowing only a narrowly defined set of anionic substrates into the mitochondrial matrix.
We are trying to understand how the specific residues in the MFT protein came to evolve and their function in the recognition of the folate transport substrates. And

3. The opportunities for therapeutics created when cancers delete specific tumor suppressor genes and alter the pattern of DNA methylation during carcinogenesis. Many of the tumor suppressor gene products are involved in multiple pathways essential to normal growth control. In particular, the p53 protein is amongst the most complex proteins in the cell, and has pivitol functions in stress-response transcription, DNA integrity and ploidy control, direct involvement in mitochondrial aspects of apoptosis, and in the assembly and integration of activities at the replication fork. Likewise, the LKB1-mTOR pathway is the richest concentration of tumor suppressor gene functions in human metabolism.
We are using homologous recombination to create cell lines marked with purification tags in specific genomic positions and mass spectrometry to isolate individual functions of these highly complex proteins, and are also developing drugs that disrupt the function of these tumor suppressor gene pathways in cell lines missing inividual functions.

Selected publications:

Bedhomme, M., Hoffmann, M., McCarthy, E.A., Gambonnet, B., Moran, R.G., Rebeille, F., Ravanel, S. Folate metabolism in plants: an Arabidopsis homolog of the mammalian mitochondrial folate transporter mediates folate import into chloroplasts. J. Biol. Chem., 280, 34823-31, 2005.

Garcia, B.A., Barber, C.M., Hake, S.B., Ptak, C., Turner, F.B., Busby, S.A., Shabanowitz, J., Moran, R.G., Allis, C.D., Hunt, D.F. Modifications of Human Histone H3 Variants during Mitosis. Biochemistry. 44:13202-13213, 2005.

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. (2007) Biochemistry, 46: 1557-67

Chattopadhyay, S., Moran, R.G., and Goldman, I.D. Pemetrexed-A Review. Mol Cancer Ther., 6:404-17, 2007.

Racanelli, A., Turner, F. B., Woodard, B.A., Taylor, S.M., and Moran, R.G. Epigenetics and promoter occlusion mechanisms controlling the choice between the dual promoters of the mouse fpgs gene. Mol Cell Biol, 28, 836-48, 2008.

Tomsho, J.W., Moran, R.G., and Coward, J.K. Concentration-dependent processivity of multiple glutamate ligations catalyzed by folylpolyglutamate synthetase. Biochemistry, August, 2008.
 

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