Multiple endocrine neoplasia type 1 (MEN1) develops in different endocrine tissues (e.g., pituitary, pancreas, thyroid) and encodes the nuclear scaffold protein menin. Endocrine tumors of the gastrointestinal tract including gastric carcinoids, pancreatic neuroendocrine tumors (pNETs) and gastrinomas, exhibit missense and nonsense mutations in the MEN1 locus, which causes loss of menin function, e.g., de-repression of gastrin gene expression. Typically, hypergastrinemia in the setting of MEN1-related gastrinomas develop primarily in the duodenum and less so in the pancreas. Therefore, the impetus for the current proposal is to understand the origin of gastrin expressing cells in the submucosa in the context of menin. Recent results have revealed that the submucosal gastrin-expressing cells in the duodenum are of neural crest and not epithelial cell origin (glial fibrillary acidic protein, GFAP+), as observed for the archived MEN1 duodenal gastrinomas, which are also GFAP+. The central hypothesis to be tested is that autocrine or paracrine factors, promote menin nuclear export and proteasome degradation culminating in induction of gastrin gene expression. A genetically- engineered mouse model that develops hypergastrinemia and carcinoid tumors is used here to study the role of nuclear menin on gastrin expression.
Aim 1 will define the conditions that regulate the nuclear export of menin required to induce gastrin gene expression.
Aim 2 will study the role of small molecule inhibitors that suppress gastrin gene expression by restricting menin translocation. A central feature of the approach is the use of a unique mouse model that exhibits the major clinical features of gastrinomas including gastrin- expressing cells in the lamina propria of the duodenum, hypergastrinemia and gastric carcinoids. The combination of acid suppression and genetic background (VillinCre:Men1FL/FL;Sst-/-) was sufficient to induce a 16-fold increase in circulating gastrin above WT control levels. Enteric glial cells will be treated with gastrin and ErbB ligands to study their effect on the nuclear export and import of menin. Leptomycin B and MG132 will be used to study the two-step loss of menin from the nucleus and then the cell by menin proteasome degradation in response to growth factor stimulation. Mass spectroscopy of the GFAP+ enteric glial cells with or without treatment will be performed to analyze the types of protein-protein interactions of menin in the nucleus versus the cytoplasm after growth factor treatment as well as mapping the phosphopeptide domains targeted by signaling pathways. Archived specimens of human duodenal and pancreatic gastrinomas will be characterized and their tumor DNA sequenced to correlate patient phenotype with the mutant menin genotype. Cell lines will be used to transfect epitope-tagged WT and mutant menin to study their function at baseline and in response to growth factors. The effect of small molecules such as octreotide and MI-503 on menin localization will be studied in vitro and in vivo. Completion of the proposed studies will demonstrate that small molecules that block the nuclear export can potentially mitigate the effect of some menin mutations.
The proposal addresses the novel concept that gastrinomas develop in the lamina propria from neural crest-derived glial cells. The impetus for glial expression of gastrin is synergistic activation of gastrin and ErbB receptors. Small molecules that stabilize nuclear menin are examined as possible therapy.
| Liu, Zhiping; Demitrack, Elise S; Keeley, Theresa M et al. (2012) IFN? contributes to the development of gastric epithelial cell metaplasia in Huntingtin interacting protein 1 related (Hip1r)-deficient mice. Lab Invest 92:1045-57 |
| Veniaminova, Natalia A; Hayes, Michael M; Varney, Jessica M et al. (2012) Conditional deletion of menin results in antral G cell hyperplasia and hypergastrinemia. Am J Physiol Gastrointest Liver Physiol 303:G752-64 |
| Mensah-Osman, Edith J; Veniaminova, Natalia A; Merchant, Juanita L (2011) Menin and JunD regulate gastrin gene expression through proximal DNA elements. Am J Physiol Gastrointest Liver Physiol 301:G783-90 |
| Tucker, Tamara P; Gray, Brian M; Eaton, Kathyrn A et al. (2010) Helicobacter pylori induction of the gastrin promoter through GC-rich DNA elements. Helicobacter 15:438-48 |
| Mensah-Osman, Edith; Labut, Ed; Zavros, Yana et al. (2008) Regulated expression of the human gastrin gene in mice. Regul Pept 151:115-22 |
| Rieder, Gabriele; Karnholz, Arno; Stoeckelhuber, Mechthild et al. (2007) H pylori infection causes chronic pancreatitis in Mongolian gerbils. World J Gastroenterol 13:3939-47 |
| Merchant, Juanita L (2005) Inflammation, atrophy, gastric cancer: connecting the molecular dots. Gastroenterology 129:1079-82 |
| Zavros, Yana; Eaton, Kathryn A; Kang, Weiqun et al. (2005) Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma. Oncogene 24:2354-66 |
| Rieder, Gabriele; Merchant, Juanita L; Haas, Rainer (2005) Helicobacter pylori cag-type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils. Gastroenterology 128:1229-42 |
| Holley-Guthrie, Elizabeth A; Seaman, William T; Bhende, Prasanna et al. (2005) The Epstein-Barr virus protein BMRF1 activates gastrin transcription. J Virol 79:745-55 |
Showing the most recent 10 out of 34 publications
