Richard G. Moran, Ph.D.
- State University of New York at Buffalo, 1974
My laboratory is interested in the biochemical and molecular phenomena underlying the selectivity of anticancer drugs and in the 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:
- We are interested in drugs that activate the function of the AMP-activated protein kinase (AMPK)- an energy-sensing control pathway capable of counteracting the loss of these tumor suppressor genes and activation of the oncogenes upstream of the mTOR pathway in non-small cell lung and other carcinomas. Most lung carcinomas have a loss of p53 function and they usually have an activation of mTORC1, the controlling kinase upstream of cap-dependent protein synthesis initiation. We have recently shown that loss or mutation of p53 causes the hyperactivation of mTORC1 and demonstrated that the mechanism of this effect is a dynamic shift of the localization of the small Ras-like protein, Rheb, at the site of active mTORC1 complexes in lysosomal membranes
- The mechanism of the antifolate pemetrexed (PTX) was shown in my laboratory to involve activation of AMPK. However, the signaling downstream of PTX-activated AMPK with that from the classical activator of AMPK, AICAR, differed: AICAR activated both canonical pathways downstream of AMPK- TSC2 activation and RAPTOR inhibition, whereas PTX caused strong RAPTOR inhibition but did not activate TSC2. Because PTX and AICAR both activated AMPK via accumulation of the purine synthesis intermediate ZMP, this was perplexing. The solution to this dilemma proved to be due to p53 biology: AICAR activated the full transactivation profile of p53, but AICAR did not. However, the phosphorylation of Raptor in PTX-treated cells proved necessary and sufficient to suppress mTORC1. This surprising difference allowed us to define the role of p53 in the mechanism whereby p53 contributes to AMPK-control of mTORC1 activity, and gave insight into why PTX is active in both p53-wild type and mutant lung carcinomas.
- Folylpolyglutamate synthetase (FPGS) controls the retention of folates in the cytosol and mitochondria of mammalian cells. In the past, our interest in FPGS led my laboratory into design and development of inhibitors of folate metabolism as cancer drugs that were trapped in tumor cells by virtue of strong substrate activity for the FPGS reaction. This metabolic trapping requires the sequential addition of several moles of glutamic acid specifically at the gamma carboxyl group of the folate side chain, with the critical step being the addition of the first two glutamates. We have become fascinated by this apparently processive process and, in collaboration with John Hackett, David Williams, and Shirley Taylor, have applied Molecular Dynamics to define the several rearrangements in the orientation of tetrahydofolate in the active site as first one, then another glutamates are added to the side chain. These simulations have proven to be an uncanny predictor of amino acid residues that are informative in mutagenesis experiments.
Chen, Y, Xie, L.Y., Windle, J., Taylor, S.M., and Moran, R.G. Humanizing mouse folate metabolism: conversion of the dual promoter mouse folylpolyglutamate synthetase gene to the human single-promoter structure. FASEB J. 28:1998-2008, 2014
Lawrence, S.A., Titus, S, Ferguson, J., Heineman, A, Taylor, S.M., and Moran, R.G. Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates. J. Biol. Chem. 289:29386-96, 2014
Agarwal, S, Bell, C Taylor, S.M. and Moran, R.G. Deletion or hot-spot mutations of p53 enhance mTORC1 activity. In press, Molecular Cancer Research, 2015.
Agarwal, S, Bell, C, Rothbart, S. and Moran, R.G. AMPK control of mTORC1 is p53 independent in pemetrexed-treated carcinoma cells. J. Biol. Chem. 290: December 4, 2015.