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J. Biol. Chem., Vol. 278, Issue 51, 50887-50896, December 19, 2003

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

ROLE OF NF-B AND AP-1^*

Heping Yang, Mamatha R. Sadda, Victor Yu, Ying Zeng, Taunia D. Lee, Xiaopeng Ou, Lixin Chen, and Shelly C. Lu

From the Division of Gastroenterology and Liver Diseases, USC Liver Disease Research Center, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine University of Southern California, Los Angeles, California 90033

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

Received for publication, July 15, 2003 , and in revised form, September 24, 2003.

^* This work was supported by National Institutes of Health Grants DK51719, AA12677, and AT1576 (to S. C. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipients of the Postdoctoral Fellowship of the Training Program in Alcoholic Liver and Pancreatic Diseases (Grant T32 AA07578).

To whom correspondence should be addressed: Division of Gastrointestinal and Liver Diseases, Hoffman Medical Research Bldg., 415, Dept. of Medicine, USC School of Medicine, 2011 Zonal Ave., Los Angeles, CA 90033. Tel.: 323-442-2441; Fax: 323-442-3234; E-mail: shellylu{at}usc.edu.

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