title: L-methionine availability regulates expression of the methionine adenosyltransferase 2A gene in human hepatocarcinoma cells: role of S-adenosylmethionine.
abstract: 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.
authors.affiliation: Laboratorio de Proteómica, Genómica y Bioinformática, and División de Hepatología y Terapia Génica, Universidad de Navarra, Facultad de Medicina, 31008 Pamplona, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.forename: M Ujue
authors.initials: MU
authors.lastname: Latasa
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.forename: Elena R
authors.initials: ER
authors.lastname: García-Trevijano
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Matías A
authors.initials: MA
authors.lastname: Avila
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008715:Methionine / Q000378:metabolism*; D008716:Methionine Adenosyltransferase / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D012436:S-Adenosylmethionine; D008715:Methionine; D008716:Methionine Adenosyltransferase