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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.