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Richard G. Moran, Ph.D. Richard G. Moran, Ph.D.
401 College Street
Massey Cancer Center
Goodwin Research Laboratories
P.O. Box 980035
Richmond, Virginia 23298-0035
Phone: (804) 828-5783
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:

Protein Translation and Cell Growth1. 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.

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