Methionine adenosyltransferase II beta subunit gene expression provides a proliferative advantage in human hepatoma.
OBJECTIVE
Of the 2 genes (MAT1A, MAT2A) encoding methionine adenosyltransferase, the enzyme that synthesizes S-adenosylmethionine, MAT1A, is expressed in liver, whereas MAT2A is expressed in extrahepatic tissues. In liver, MAT2A expression associates with growth, dedifferentiation, and cancer. Here, we identified the beta subunit as a regulator of proliferation in human hepatoma cell lines. The beta subunit has been cloned and shown to lower the K(m) of methionine adenosyltransferase II alpha2 (the MAT2A product) for methionine and to render the enzyme more susceptible to S-adenosylmethionine inhibition.


METHODS
Methionine adenosyltransferase II alpha2 and beta subunit expression was analyzed in human and rat liver and hepatoma cell lines and their interaction studied in HuH7 cells. beta Subunit expression was up- and down-regulated in human hepatoma cell lines and the effect on DNA synthesis determined.


RESULTS
We found that beta subunit is expressed in rat extrahepatic tissues but not in normal liver. In human liver, beta subunit expression associates with cirrhosis and hepatoma. beta Subunit is expressed in most (HepG2, PLC, and Hep3B) but not all (HuH7) hepatoma cell lines. Transfection of beta subunit reduced S-adenosylmethionine content and stimulated DNA synthesis in HuH7 cells, whereas down-regulation of beta subunit expression diminished DNA synthesis in HepG2. The interaction between methionine adenosyltransferase II alpha2 and beta subunit was demonstrated in HuH7 cells.


CONCLUSIONS
Our findings indicate that beta subunit associates with cirrhosis and cancer providing a proliferative advantage in hepatoma cells through its interaction with methionine adenosyltransferase II alpha2 and down-regulation of S-adenosylmethionine levels.
Martínez-Chantar
Maria L
ML
División de Hepatología y Terapia Génica, Departamento de Medicina Interna, Universidad de Navarra, Pamplona, Spain.
García-Trevijano
Elena R
ER
Latasa
M Ujue
MU
Martín-Duce
Antonio
A
Fortes
Puri
P
Caballería
Juan
J
Avila
Matías A
MA
Mato
José M
JM
D006528:Carcinoma, Hepatocellular; D002455:Cell Division / Q000235:genetics; D004247:DNA / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000503:physiopathology; D008113:Liver Neoplasms; D008716:Methionine Adenosyltransferase / Q000235:genetics*; D010641:Phenotype; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000201:enzymology
D004247:DNA; D008716:Methionine Adenosyltransferase