Abstract

Activation of antimetabolites to metabolites which are retained in cells and mitochondria is catalyzed by the enzyme folylpolyglutamate synthetase (FPGS). Transcription of the FPGS gene in mouse tissues is regulated by the tissue-specific activation of an upstream promoter only in differentiated tissues which serve as specialized organs of folate metabolism, and in all normal and malignant dividing cell populations from a downstream promoter. The recriprical regulation of these two promoters will be studied as will the function of the isoform of FPGS transcribed from the upstream promoter. The intracellular trafficing of FPGS is gaurenteed by the transcription of either upstream or downstream promoter in a manner which produces both a transcript for FPGS which traffices to the cytosol and a second form which traffices to the mitochondrial compartment. The dynamics and functions of this trafficing will be studied. Finally, the role of specific peptides in the enzyme mechanism will be determined.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA039687-18
Application #
6431348
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
1985-09-30
Project End
2007-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
18
Fiscal Year
2002
Total Cost
$295,925
Indirect Cost

  Institution

Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298

  Publications

Yang, Chen; Xie, Lin-Ying; Windle, Jolene J et al. (2014) Humanizing mouse folate metabolism: conversion of the dual-promoter mouse folylpolyglutamate synthetase gene to the human single-promoter structure. FASEB J 28:1998-2008
Lawrence, Scott A; Titus, Steven A; Ferguson, Jennifer et al. (2014) Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates. J Biol Chem 289:29386-96
Bareford, M Danielle; Park, Margaret A; Yacoub, Adly et al. (2011) Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Cancer Res 71:4955-67
Bareford, M Danielle; Hamed, Hossein A; Tang, Yong et al. (2011) Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Autophagy 7:1261-2
Racanelli, Alexandra C; Turner, Fiona B; Xie, Lin-Ying et al. (2008) A mouse gene that coordinates epigenetic controls and transcriptional interference to achieve tissue-specific expression. Mol Cell Biol 28:836-48
Tomsho, John W; Moran, Richard G; Coward, James K (2008) Concentration-dependent processivity of multiple glutamate ligations catalyzed by folylpoly-gamma-glutamate synthetase. Biochemistry 47:9040-50
Chattopadhyay, Shrikanta; Moran, Richard G; Goldman, I David (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther 6:404-17
Andreassi 2nd, John L; Moran, Richard G (2002) Mouse folylpoly-gamma-glutamate synthetase isoforms respond differently to feedback inhibition by folylpolyglutamate cofactors. Biochemistry 41:226-35
Turner, F B; Taylor, S M; Moran, R G (2000) Expression patterns of the multiple transcripts from the folylpolyglutamate synthetase gene in human leukemias and normal differentiated tissues. J Biol Chem 275:35960-8
Zhao, R; Titus, S; Gao, F et al. (2000) Molecular analysis of murine leukemia cell lines resistant to 5, 10-dideazatetrahydrofolate identifies several amino acids critical to the function of folylpolyglutamate synthetase. J Biol Chem 275:26599-606

Showing the most recent 10 out of 18 publications