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J. Biol. Chem., Vol. 278, Issue 22, 19885-19890, May 30, 2003

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L-Methionine Availability Regulates Expression of the Methionine Adenosyltransferase 2A Gene in Human Hepatocarcinoma Cells

ROLE OF S-ADENOSYLMETHIONINE^*

Maria L. Martínez-Chantar   ¶, M. Ujue Latasa   ||, Marta Varela-Rey  ¶, Shelly C. Lu **, Elena R. García-Trevijano , José M. Mato   and Matías A. Avila   

From the Laboratorio de Proteómica, Genómica y Bioinformática, and División de Hepatología y Terapia Génica, Universidad de Navarra, Facultad de Medicina, 31008 Pamplona, Spain and the ^**Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California 90033

In mammals, methionine adenosyltransferase (MAT), the enzyme responsible for S-adenosylmethionine (AdoMet) synthesis, is encoded by two genes, MAT1A and MAT2A. In liver, MAT1A expression is associated with high AdoMet levels and a differentiated phenotype, whereas MAT2A expression is associated with lower AdoMet levels and a dedifferentiated phenotype. In the current study, we examined regulation of MAT2A gene expression by L-methionine availability using HepG2 cells. In L-methionine-deficient cells, MAT2A gene expression is rapidly induced, and methionine adenosyltransferase activity is increased. Restoration of L-methionine rapidly down-regulates MAT2A mRNA levels; for this effect, L-methionine needs to be converted into AdoMet. This novel action of AdoMet is not mediated through a methyl transfer reaction. MAT2A gene expression was also regulated by 5'-methylthioadenosine, but this was dependent on 5'-methylthioadenosine conversion to methionine through the salvage pathway. The transcription rate of the MAT2A gene remained unchanged during L-methionine starvation; however, its mRNA half-life was significantly increased (from 100 min to more than 3 h). The effect of L-methionine withdrawal on MAT2A mRNA stabilization requires both gene transcription and protein synthesis. We conclude that MAT2A gene expression is modulated as an adaptive response of the cell to L-methionine availability through its conversion to AdoMet.

Received for publication, November 13, 2002 , and in revised form, March 20, 2003.

^* This work was supported by National Center for Complementary and Alternative Medicine, National Institutes of Health (NIH), Grant R01 AT-1576 (to S. C. L., J. M. M., and M. A. A.); NIAA, NIH, Grants R01 AA-12677 and R01 AA013847 (to S. C. L., J. M. M., and M. A. A.), Plan Nacional de I+D Grant 99/0038 (to J. M. M.); Ministerio de Sanidad y Consumo Grant FIS 01/0712 (to M. A. A.); a grant from the Fundación Iñigo Alvarez de Toledo (to M. A. A.); Gobierno de Navarra Grants 681/2000 and 394/2001 (to J. M. M. and M. A. A., respectively); NIH Grant R01 DK-51719 (to S. C. L.); Instituto de Salud Carlos III Grants G03/015 Red Temática de Investigación Cooperativa and C03/C02 Red Nacional de Investigación en Hepatología y Gastroenterología (to J. M. M. and M. A. A.); and Grant PI0220369 from the Ministeriode Sanidad y Consumo (to E. R. G. T.). 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.

Both authors contributed equally to this work.

^¶ Fellow of the Universidad de Navarra.

^|| Fellow of the Spanish Ministerio de Ciencia y Tecnología.

Both authors share senior authorship.

To whom correspondence should be addressed: Laboratorio de Proteómica, Genómica y Bioinformática, División de Hepatología y Terapia Génica, Facultad de Medicina, Universidad de Navarra, 31008 Pamplona, Spain. Tel.: 34-948-425678; Fax: 34-948-425677; E-mail: maavila{at}unav.es.

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