L-methionine availability regulates expression of the methionine adenosyltransferase 2A gene in human hepatocarcinoma cells: role of S-adenosylmethionine.
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.
Martínez-Chantar
Maria L
ML
Laboratorio de Proteómica, Genómica y Bioinformática, and División de Hepatología y Terapia Génica, Universidad de Navarra, Facultad de Medicina, 31008 Pamplona, Spain.
Latasa
M Ujue
MU
Varela-Rey
Marta
M
Lu
Shelly C
SC
García-Trevijano
Elena R
ER
Mato
José M
JM
Avila
Matías A
MA
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
D012333:RNA, Messenger; D012436:S-Adenosylmethionine; D008715:Methionine; D008716:Methionine Adenosyltransferase