Induction of Human Methionine Adenosyltransferase 2A Expression by Tumor Necrosis Factor Î

• Published in: The Journal of biological chemistry Vol. 278; no. 51; p. 50887
• Main Authors: Heping Yang, Mamatha R. Sadda, Victor Yu, Ying Zeng, Taunia D. Lee, Xiaopeng Ou, Lixin Chen, Shelly C. Lu
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 19.12.2003
• 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-κB and AP-1 elements, and the present study examined whether they regulate MAT2A promoter activity. We found nuclear binding of NF-κB and AP-1 to the MAT2A promoter increased in HCC. Tumor necrosis factor α (TNFα), which activates both NF-κB and AP-1, increased MAT2A expression in a dose- and time-dependent manner, binding of both NF-κB and AP-1 to the MAT2A promoter and MAT2A promoter activity, with the latter effect blocked by site-directed mutagenesis of the NF-κB and AP-1 binding sites. Blocking NF-κB with IκB super-repressor or AP-1 with dominant-negative c-Jun led to decreased basal MAT2A expression and prevented the TNFα-induced increase in MAT2A expression. Although blocking NF-κB had no influence on the ability of TNFα to increase AP-1 nuclear binding, blocking AP-1 with dominant-negative c-Jun prevented the TNFα-mediated increase in NF-κB binding. In conclusion, both NF-κB and AP-1 are required for basal MAT2A expression in HepG2 cells and mediate the increase in MAT2A expression in response to TNFα treatment. Increased trans -activation of these two sites also contributes to MAT2A up-regulation in HCC.