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Subhi AL , Diegelman P , Porter CW , Tang BQ , Lu ZCJ , Markham GD , Kruger WD
Methylthioadenosine phosphorylase regulates ornithine decarboxylase by production of downstream metabolites
Journal of Biological Chemistry. 2003 Dec;278(50) :49868-49873
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The gene encoding methylthioadenosine phosphorylase (MTAP), the initial enzyme in the methionine salvage pathway, is deleted in a variety of human tumors and acts as a tumor suppressor gene in cell culture (Christopher, S. A., Diegelman, P., Porter, C. W., and Kruger, W. D. (2002) Cancer Res. 62, 6639 - 6644). Overexpression of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) is frequently observed in tumors and has been shown to be tumorigenic in vitro and in vivo. In this paper, we demonstrate a novel regulatory pathway in which the methionine salvage pathway products inhibit ODC activity. We show that in Saccharomyces cerevisiae the MEU1 gene encodes MTAP and that Meu1Delta cells have an 8-fold increase in ODC activity, resulting in large elevations in polyamine pools. Mutations in putative salvage pathway genes downstream of MTAP also cause elevated ODC activity and elevated polyamines. The addition of the penultimate salvage pathway compound 4-methylthio-! 2-oxobutanoic acid represses ODC levels in both MTAP-deleted yeast and human tumor cell lines, indicating that 4-methylthio-2-oxobutanoic acid acts as a negative regulator of polyamine biosynthesis. Expression of MTAP in MTAP-deleted MCF-7 breast adenocarcinoma cells results in a significant reduction of ODC activity and reduction in polyamine levels. Taken together, our results show that products of the methionine salvage pathway regulate polyamine biosynthesis and suggest that MTAP deletion may lead to ODC activation in human tumors.
English Article KeyWords Plus: METHIONINE SALVAGE PATHWAY; SACCHAROMYCES-CEREVISIAE; KLEBSIELLA-PNEUMONIAE; HISTONE ACETYLTRANSFERASE; HOMOZYGOUS DELETIONS; S-ADENOSYLMETHIONINE; CELL-GROWTH; RAT-LIVER; GENE; 5'-METHYLTHIOADENOSINE Kruger, WD; *Fox* *Chase* Canc Ctr, Div Populat Sci, 333 Cottman Ave, Philadelphia, PA 19111 USA. Research Addresses: *Fox* *Chase* Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. *Fox* *Chase* Canc Ctr, Div Basic Sci, Philadelphia, PA 19111 USA. Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA. Cited References: AUVINEN M, 1992, NATURE, V360, P355 BACKLUND PS, 1982, J BIOL CHEM, V257, P4196 BACKLUND PS, 1981, J BIOL CHEM, V256, P1533 BACKLUND PS, 1982, BIOCHEM BIOPH RES CO, V108, P687 BALASUNDARAM D, 1991, P NATL ACAD SCI USA, V88, P5872 BALAKRISHNAN R, 1993, J BIOL CHEM, V268, P24792 BATOVA A, 1996, BLOOD, V88, P3083 BRACHMANN CB, 1998, YEAST, V14, P115 CHEN ZH, 1997, MOL PHARMACOL, V52, P903 CHRISTOPHER SA, 2002, CANCER RES, V62, P6639 COFFINO P, 2001, NAT REV MOL CELL BIO, V2, P188 COHEN SS, 1998, GUIDE POLYAMINES, P296 COHN MS, 1983, METHOD ENZYMOL, V94, P231 CONE MC, 1982, J BACTERIOL, V151, P510 DAI Y, 1999, J BIOL CHEM, V274, P1193 DELLARAGIONE F, 1995, ONCOGENE, V10, P827 DIBNER JJ, 1990, J NUTR, V120, P553 DONOVIEL MS, 1996, GENETICS, V143, P1137 FERRO AJ, 1981, BIOCHEM BIOPH RES CO, V100, P523 FURFINE ES, 1988, J BIOL CHEM, V263, P9598 GARCIACASTELLANO JM, 2002, CLIN CANCER RES, V8, P782 GIAEVER G, 2002, NATURE, V418, P387 GUPTA R, 2001, P NATL ACAD SCI USA, V98, P10620 HARLOW E, 1988, ANTIBODIES LAB MANUA HOBBS CA, 2000, J CELL BIOCHEM, V77, P345 HOBBS CA, 2002, CANCER RES, V62, P67 KUO MH, 1998, BIOESSAYS, V20, P615 MARCHITTO KS, 1985, J GEN MICROBIOL, V131, P2153 MEGOSH L, 1995, CANCER RES, V55, P4205 MYERS RW, 1993, J BIOL CHEM, V268, P24785 MYERS RW, 1990, J BIOL CHEM, V265, P16913 NOBORI T, 1996, P NATL ACAD SCI USA, V93, P6203 NOBORI T, 1991, CANCER RES, V51, P3193 OBRIEN TG, 1997, CANCER RES, V57, P2630 PEGG AE, 1981, BIOCHEM J, V194, P79 PEGG AE, 1988, CANCER RES, V48, P759 POLLARD KJ, 1999, EMBO J, V18, P5622 QUASH G, 1995, BIOCHEM J 3, V305, P1017 SCHIPPER RG, 2000, SEMIN CANCER BIOL, V10, P55 SCHMID M, 1998, ONCOGENE, V17, P2669 SHERMAN F, 1991, METHOD ENZYMOL, V194, P3 SIKORSKI RS, 1989, GENETICS, V122, P19 STADLER WM, 1996, UROL RES, V24, P239 TANG BQ, 2000, CANCER RES, V60, P5543 THOMAS D, 2000, J BIOL CHEM, V275, P40718 TOOHEY JI, 1978, BIOCHEM BIOPH RES CO, V83, P27 TOTH C, 1999, J BIOL CHEM, V274, P25921 TRACKMAN PC, 1981, BIOCHEM BIOPH RES CO, V103, P1238 TRACKMAN PC, 1983, J BIOL CHEM, V258, P6717 TYAGI AK, 1983, METHOD ENZYMOL, V94, P135 VUJCIC S, 2000, J BIOL CHEM, V275, P38319 WILLIAMSASHMAN HG, 1982, BIOCHEM PHARMACOL, V31, P277 WRAY JW, 1995, J BIOL CHEM, V270, P3147 Number of cited references: 53 Number of times cited: 0 Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC; 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA. 0021-9258