Two genes (MAT1A and MAT2A) encode for methionine adenosyltransferase (MAT), an essential cellular enzyme responsible for S-adenosylmethionine biosynthesis. MAT1A is expressed mostly in the liver, whereas MAT2A is widely distributed. We showed a switch from MAT1A to MAT2A expression in human hepatocellular carcinoma (HCC), which facilitates cancer cell growth. Using DNase I footprinting analysis, we previously identified a region in the MAT2A promoter protected from DNase I digestion in HCC. This region contains NF-B and AP-1 elements, and the present study examined whether they regulate MAT2A promoter activity. We
Methionine adenosyltransferase (MAT)1 is an essential cellular enzyme that catalyzes the formation of S-adenosylmethionine (SAMe), the principal biological methyl donor and the ultimate source of the propylamine moiety used in polyamine biosynthesis (1, 2). In mammals, two different genes, MAT1A and MAT2A, encode for two homologous MAT catalytic subunits, ␣1 and ␣2 (3-5). MAT1A is expressed mostly in liver, and it encodes the ␣1 subunit found in two native MAT isozymes, which are either a dimer (MAT III) or tetramer (MAT I) of this single subunit (5). MAT2A encodes for a catalytic subunit (␣2) found in a native MAT isozyme (MAT II), which is associated with a catalytically inactive regulatory subunit () in lymphocytes encoded by yet a third gene (5, 6). MAT2A is widely distributed (3-5). MAT2A also predominates in the fetal liver and is progressively replaced by MAT1A during liver development (7,8). In adult liver, increased expression of MAT2A is associated with rapid growth or de-differentiation of the liver (9 -11). Using a cell line model that differs only in the type of MAT expressed, we demonstrated that a switch in MAT expression in liver cancer (from MAT1A to MAT2A) plays an important pathogenetic role by facilitating liver cancer growth (12). The influence of MAT expression on liver growth and injury was further demonstrated using a MAT1A knockout mouse model (13,14). In this model, absence of hepatic MAT1A is compensated by induction of MAT2A. These animals exhibit chronic hepatic SAMe deficiency, are prone to liver injury and develop spontaneous hepatocellular carcinoma (HCC) (13,14).Given the importance of MAT expression in liver disease and cancer, we have been interested in understanding transcriptional regulation of MAT genes. We characterized the promoter region of both human MAT genes (15, 16) and showed previously that in human HCC, both promoter hypomethylation (17) and increased expression of c-Myb and Sp1 with subsequent trans-activation of the MAT2A promoter contribute to transcriptional up-regulation of MAT2A in HCC (18). In the latter work we described increased protein binding to the MAT2A promoter region (Ϫ354 to Ϫ312) in HCC as compared with normal liver (18). Two other consensus elements in this DNase I protected region are nuclear factor kappa B (NF-B) and activator protein 1 (AP-1). We had previously observed that nuclear binding of NF-B and AP-1 to the promoter of huma...
