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Richard G. Moran,
Ph.D. Professor 401 College Street Massey Cancer Center Goodwin Research Laboratories 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 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
PI3kinase-Akt-mTOR pathway is the richest concentration of tumor
suppressor gene functions in human metabolism. We are interested in drugs
that activate the function of the AMP-dependent protein kinase- a critical
link to pharmacologically re-establishing the function of the tumor
suppressor genes in the mTOR pathway lost in non-small cell lung and other
carcinomas. The linkage between AMPK and the p53 tumor suppressor gene is
one of the most interesting and complex interactions in current tumor
biology.
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,
their function in the recognition of the folate transport substrates, and
how the “floor’ of the transport channel opens and closes upon positioning
of substrate. And
3. 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.
Selected publications:
Shock LS, Thakkar PV, Peterson EJ, Moran RG, and Taylor SM.
(2011) DNA methyltransferase 1, cytosine methylation, and cytosine
hydroxymethylation in mammalian mitochondria.
Proc Natl Acad Sci U S A. [Epub ahead of print]
Rothbart SB,
Racanelli AC, and Moran RG. (2010) Pemetrexed indirectly activates the
metabolic kinase AMPK in human carcinomas.
Cancer Res. 70(24):10299-309.
Racanelli AC, Rothbart SB, Heyer
CL, and Moran RG. (2009) Therapeutics by cytotoxic metabolite accumulation:
pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of
rapamycin inhibition. Cancer Res.
69(13):5467-74.
Racanelli AC, Turner FB, Xie LY, Taylor SM, and Moran
RG. (2008) A mouse gene that coordinates epigenetic controls and
transcriptional interference to achieve tissue-specific expression.
Mol Cell Biol. 28(2):836-48.
Tomsho JW, Moran RG, and Coward JK.
(2008) Concentration-dependent processivity of multiple glutamate ligations
catalyzed by folylpolyglutamate synthetase. Biochemistry 47:9040-50.