Transcriptional Control of Gastrin

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

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 is 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 MEN! gene product menin presumably play a central role in activation of the gastrin gene; whereas, the mechanisms by which gastrin is overexpressed in colon cancer are less well defined, but likely involvesactivated rus 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, Sp 1 and ZBP-89, to known cancer pathways, e.g.,mcnin, p53 will be examined. Spl and ZBP-89 are both Kruppel-iype zinc finger transcription factors that bind to the human gastrin promoter. Whether Spl 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 Sp 1 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 Spl in gastrin gene expression, the Spl gene will be disrupted in the antral G cell using Cre-Lox technology. Second, transgenic mouse lines expressing a human gastrin- Pgalactosidase 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 Thl 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. 'ERFORMANCE SITE(S) (organization, city, state) University of Michigan, Ann Arbor, MI KEY PERSONNEL. See instructions on Page 11. Use continuationpages as neededtoprovide the required information in the format shown below. Name Organization Role on Project Juanita Merchant UniversityOf Michigan PI Sergey Chupreta University Of Michigan Postdoc Gabriele Rieder University Of Michigan Postdoc Linda Samuelson UniversityOf Michigan Consultant Sally Camper UniversityOf Michigan Consultant PHS 398(Rev. 5/95) Page 2 B B Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. CC Principal Investigator/Program Director (Last, first, middle): Merchant. Juatlita Type the name of the principal investigatorTpfogram director at the top of each printed page and elm continuation page. (For type specifications, see instructions on page 6.) RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,