HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 50, 49868-49873, December 12, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/50/49868    most recent M308451200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Subhi, A. L. Articles by Kruger, W. D. Search for Related Content PubMed PubMed Citation Articles by Subhi, A. L. Articles by Kruger, W. D. Social Bookmarking                      What's this?

Methylthioadenosine Phosphorylase Regulates Ornithine Decarboxylase by Production of Downstream Metabolites^*

Ahmad L. Subhi, Paula Diegelman, Carl W. Porter, Baiqing Tang, Zichun J. Lu¶, George D. Markham¶, and Warren D. Kruger||

From the Divisions of Population Science and ^¶Basic Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 and the Roswell Park Cancer Institute, Pharmacology and Therapeutics Department, Buffalo, New York 14263

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 Meu1 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.

Received for publication, August 1, 2003 , and in revised form, September 11, 2003.

^* This work was supported by United States Army Grant DAMD1797-1-7707, United States Public Health Service Grant CA-22153, National Institutes of Health Core Grant CA-06927, and an appropriation from the Commonwealth of Pennsylvania. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111-2497. Tel.: 215-728-3030; Fax: 215-214-1623; E-mail: wd_kruger{at}fccc.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				P. Leprohon, D. Legare, F. Raymond, E. Madore, G. Hardiman, J. Corbeil, and M. Ouellette Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum Nucleic Acids Res., April 1, 2009; 37(5): 1387 - 1399. [Abstract] [Full Text] [PDF]

				M. G. Malkowski, E. Quartley, A. E. Friedman, J. Babulski, Y. Kon, J. Wolfley, M. Said, J. R. Luft, E. M. Phizicky, G. T. DeTitta, et al. Blocking S-adenosylmethionine synthesis in yeast allows selenomethionine incorporation and multiwavelength anomalous dispersion phasing PNAS, April 17, 2007; 104(16): 6678 - 6683. [Abstract] [Full Text] [PDF]

				C. Hellerbrand, M. Muhlbauer, S. Wallner, M. Schuierer, I. Behrmann, F. Bataille, T. Weiss, J. Scholmerich, and A.-K. Bosserhoff Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma Carcinogenesis, January 1, 2006; 27(1): 64 - 72. [Abstract] [Full Text] [PDF]

				K. Stamatakis, F. J. Sanchez-Gomez, and D. Perez-Sala Identification of Novel Protein Targets for Modification by 15-Deoxy-{Delta}12,14-Prostaglandin J2 in Mesangial Cells Reveals Multiple Interactions with the Cytoskeleton J. Am. Soc. Nephrol., January 1, 2006; 17(1): 89 - 98. [Abstract] [Full Text] [PDF]

				M. K. Chattopadhyay, C. W. Tabor, and H. Tabor Studies on the regulation of ornithine decarboxylase in yeast: Effect of deletion in the MEU1 gene PNAS, November 8, 2005; 102(45): 16158 - 16163. [Abstract] [Full Text] [PDF]

				C. Zer and G. Chanfreau Regulation and Surveillance of Normal and 3'-Extended Forms of the Yeast Aci-reductone Dioxygenase mRNA by RNase III Cleavage and Exonucleolytic Degradation J. Biol. Chem., August 12, 2005; 280(32): 28997 - 29003. [Abstract] [Full Text] [PDF]

				W. Choi, E. W. Gerner, L. Ramdas, J. Dupart, J. Carew, L. Proctor, P. Huang, W. Zhang, and S. R. Hamilton Combination of 5-Fluorouracil and N1,N11-Diethylnorspermine Markedly Activates Spermidine/Spermine N1-Acetyltransferase Expression, Depletes Polyamines, and Synergistically Induces Apoptosis in Colon Carcinoma Cells J. Biol. Chem., February 4, 2005; 280(5): 3295 - 3304. [Abstract] [Full Text] [PDF]

				A. L. Subhi, B. Tang, B. R. Balsara, D. A. Altomare, J. R. Testa, H. S. Cooper, J. P. Hoffman, N. J. Meropol, and W. D. Kruger Loss of Methylthioadenosine Phosphorylase and Elevated Ornithine Decarboxylase Is Common in Pancreatic Cancer Clin. Cancer Res., November 1, 2004; 10(21): 7290 - 7296. [Abstract] [Full Text] [PDF]

				M. Bumann, S. Djafarzadeh, A. E. Oberholzer, P. Bigler, M. Altmann, H. Trachsel, and U. Baumann Crystal Structure of Yeast Ypr118w, a Methylthioribose-1-phosphate Isomerase Related to Regulatory eIF2B Subunits J. Biol. Chem., August 27, 2004; 279(35): 37087 - 37094. [Abstract] [Full Text] [PDF]