The long-term goals of this proposal are to identify and characterize novel paradigms of gastrointestinal transformation. Our initial objectives are to study the process of cancer development in the stomach where predisposing factors include the absence of gastric acid secretion (achlorhydria) and longstanding Helicobacter pylori infection. The current paradigms describing transformation in the stomach have not adequately described in molecular terms how these predisposing factors cause disease. Rather current understanding primarily reflects direct application of what is known regarding transformation in the colon. We have taken the approach that the stomach expresses several known growth factors, including EGF receptor ligands that increase with gastric transformation. The zinc finger transcription factor called ZBP-89 is a potent repressor of EGF receptor activation and inhibits transcription of the ornithine decarboxylase promoter and the stomach specific gene gastrin through specific CACCC/GTGGG elements. Recently, we have found that ZBP-89 is a transcriptional activator of the cell cycle inhibitor p21 in the presence of sodium butyrate. ZBP-89 resides on chromosome 3q21 which is a site of reciprocal translocations in both leukemia and gastric cancer. ZBP-89 is differentially expressed in some gastric cancers and somatic mutations of its C- terminal domain have been identified in gastrointestinal cancers. Therefore the specific aims of this application are to examine the role of ZBP-89 in cell cycle progression and proliferation; to characterize related ZBP-89 molecules and to examine its relevance in vivo by targeted gene disruption. Recombinant ZBP- 89 and various mutations of this protein will be used to examine how this transcription factor regulates cellular proliferation in transfected cells. Mutations of ZBP-89 that have lost their ability to regulate cell growth will be created to determine whether this protein interacts with known cell cycle regulators. Inactive mutants that bind DNA will be subcloned into an inducible promoter and used to disrupt ZBP-89 function in cell lines in a dominant negative manner. The domain mediating cell cycle regulation will be used to isolate and clone interacting molecules. Related ZBP-89 molecules will be identified by low stringency screening and characterized in terms of their ability to stimulate or inhibit cell growth. To study the role of ZBP-89 in vivo, the mouse ZBP-89 gene will be targeted for disruption by inserting the bacterial beta-galactosidase gene into the mouse locus. Insertion of the beta-galactosidase gene will permit the study of ZBP-89 expression during mouse development and to assess in which tissues ZBP-89 is critical for function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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May, Michael K
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Ocadiz-Ruiz, Ramon; Photenhauer, Amanda L; Hayes, Michael M et al. (2017) ZBP-89 function in colonic stem cells and during butyrate-induced senescence. Oncotarget 8:94330-94344
Essien, Bryan E; Sundaresan, Sinju; Ocadiz-Ruiz, Ramon et al. (2016) Transcription Factor ZBP-89 Drives a Feedforward Loop of ?-Catenin Expression in Colorectal Cancer. Cancer Res 76:6877-6887
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Grasberger, Helmut; Gao, Jun; Nagao-Kitamoto, Hiroko et al. (2015) Increased Expression of DUOX2 Is an Epithelial Response to Mucosal Dysbiosis Required for Immune Homeostasis in Mouse Intestine. Gastroenterology 149:1849-59
Li, Xiangen; Romain, Rachael D; Park, Dongsu et al. (2014) Stress hematopoiesis is regulated by the Krüppel-like transcription factor ZBP-89. Stem Cells 32:791-801
Grasberger, Helmut; Chang, Lin; Shih, Wendy et al. (2013) Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes. Am J Gastroenterol 108:1766-74
Grasberger, Helmut; El-Zaatari, Mohamad; Dang, Duyen T et al. (2013) Dual oxidases control release of hydrogen peroxide by the gastric epithelium to prevent Helicobacter felis infection and inflammation in mice. Gastroenterology 145:1045-54
Essien, Bryan E; Grasberger, Helmut; Romain, Rachael D et al. (2013) ZBP-89 regulates expression of tryptophan hydroxylase I and mucosal defense against Salmonella typhimurium in mice. Gastroenterology 144:1466-77, 1477.e1-9
Ye, Cai Guo; Chen, George G; Ho, Rocky L K et al. (2013) Epigenetic upregulation of Bak by ZBP-89 inhibits the growth of hepatocellular carcinoma. Biochim Biophys Acta 1833:2970-2979
Mazuy, Claire; Ploton, Maheul; Eeckhoute, Jérôme et al. (2013) Palmitate increases Nur77 expression by modulating ZBP89 and Sp1 binding to the Nur77 proximal promoter in pancreatic ?-cells. FEBS Lett 587:3883-90

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