Induction of human methionine adenosyltransferase 2A expression by tumor necrosis factor alpha. Role of NF-kappa B and AP-1

• Published in: The Journal of biological chemistry 2003-12, Vol.278 (51), p.50887-50896
• Main Authors: Yang, Heping, Sadda, Mamatha R, Yu, Victor, Zeng, Ying, Lee, Taunia D, Ou, Xiaopeng, Chen, Lixin, Lu, Shelly C
• Format: Article
• Language: English
• Subjects: binding sites; Binding Sites - genetics; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - pathology; Gene Expression Regulation; Humans; Liver - cytology; Liver - enzymology; Liver - pathology; MAT1A gene; MAT2A gene; Methionine Adenosyltransferase - biosynthesis; Methionine Adenosyltransferase - genetics; NF-kappa B - physiology; Promoter Regions, Genetic; Proto-Oncogene Proteins c-jun - physiology; S-adenosylmethionine; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - physiology; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M307600200

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-kappa B and AP-1 elements, and the present study examined whether they regulate MAT2A promoter activity. We found nuclear binding of NF-kappa B and AP-1 to the MAT2A promoter increased in HCC. Tumor necrosis factor alpha (TNFalpha), which activates both NF-kappa B and AP-1, increased MAT2A expression in a dose- and time-dependent manner, binding of both NF-kappa B and AP-1 to the MAT2A promoter and MAT2A promoter activity, with the latter effect blocked by site-directed mutagenesis of the NF-kappa B and AP-1 binding sites. Blocking NF-kappa B with I kappa B super-repressor or AP-1 with dominant-negative c-Jun led to decreased basal MAT2A expression and prevented the TNF alpha-induced increase in MAT2A expression. Although blocking NF-kappa B had no influence on the ability of TNF alpha to increase AP-1 nuclear binding, blocking AP-1 with dominant-negative c-Jun prevented the TNF alpha-mediated increase in NF-kappa B binding. In conclusion, both NF-kappa B and AP-1 are required for basal MAT2A expression in HepG2 cells and mediate the increase in MAT2A expression in response to TNF alpha treatment. Increased trans-activation of these two sites also contributes to MAT2A up-regulation in HCC.