Transcriptional Control of Gastrin

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): The hormone gastrin is secreted from the antrum of the stomach and stimulates acid secretion coordinately with histamine and acetylcholine. Changes in the rate of transcription from the gastrin gene occur with fasting and refeeding, but more dramatically with an increase in gastric pH. Thus, it has been concluded that gastrin gene expression is regulated, albeit indirectly, by changes in gastric pH. With the current understanding that gastrin gene expression increases with H. pylori infection, it has now been proposed that gastrin in regulated by bacterial proteins and/or cytokines. In addition, transcription of the gastrin gene is upregulated during neoplastic transformation, e.g., in gastrinomas and colon cancers. With respect to gastrinomas, mutations in the MEN1 gene product, menin, presumably play a central role in activation of the gastrin gene; the mechanisms by which gastrin is overexpressed in colon cancer are less well defined, but likely involves activated ras mutations. Overall, the studies proposed in the continuation of this grant will further characterize the transcriptional elements and factors that bind the human gastrin promoter, then test these elements in transgenic mouse lines. First, the relationship of two zinc finger transcription factors, Sp1 and ZBP-89, to known cancer pathways, e.g., menin, p53 will be examined. Sp1 and ZBP-89 are both Kruppel-type zinc finger transcription factors that bind to the human gastrin promoter. Whether Sp1 interacts with members of the Jun transcription factor family will be explored in co-precipitation and transfection assays. Recently, ZBP-89 has been shown to interact with Sp1 and p53. Therefore, whether transcriptional repression of gastrin is mediated through the cooperation of ZBP-89 with p53 will be examined. To test directly the role of Sp1 in gastrin gene expression, the Sp1 gene will be disrupted in the antral G cell using Cre-Lox technology. Second, transgenic mouse lines expressing a human gastrin-beta galactosidase reporter in the antral G cell will be studied. The expression of the reporter gene from the wild type human gastrin promoter will be compared to a transgene containing mutations in specific DNA regulatory elements. Third, how components of bacterial colonization stimulate gastrin gene expression will be studied by examining how the H. pylori CagA protein stimulates gastrin. Fourth, how the H. pylori-induced Th1 lymphocyte response with elevated tissue levels of interferon gamma stimulates gastrin gene expression will be explored. Collectively, these studies will dissect the signaling pathways and factors capable of regulating gastrin and further validate these pathways through in vivo studies in transgenic mice.