S-adenosylmethionine synthetase (SAMS) catalyzes the formation of S-adenosylmethionine, the principal biological methyl donor, which is essential to normal cell function. There are two forms of SAMS, liver-specific and non-hepatic, which are the products of two different genes. The normal mature liver expresses mainly liver-specific SAMS; however, various human-derived liver cancer cell lines and hepatoma tissues resected from patients show an absence of liver-specific SAMS due to a lack of gene transcription; however, non-hepatic SAMS was induced. Thus, there was a higher SAMS activity at physiologic methionine concentrations and this observation is thought to possibly offer a growth advantage. Recent preliminary data have shown that HuH-7 cells which express non-hepatic SAMS have higher rates of growth and DNA synthesis than those expressing mainly liver-specific SAMS. The applicant has hypothesized that the difference in SAMS gene expression in liver cancer is due to the presence of different transcriptional factors with a switch in gene expression contributing to the carcinogenesis. The promoter sequence of both human SAMS and the subunit structure and functional regulation of non-hepatic SAMS are unknown. A variety of sophisticated techniques will be utilized to examine the four specific aims of this application. These are (1) to evaluate the molecular regulation of human SAMS, (2) the functional regulation of non-hepatic SAMS, (3) the significance of the change in SAMS gene expression in liver cancer, and (4) the potential of SAMS inhibitors as chemotherapy against liver cancer. It is hoped that these studies would enhance our knowledge of a key cellular enzyme and offer possible therapeutic approaches against a cancer that currently lacks effective treatment.
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