Hypergastrinemia has enormous clinical implications with respect to acid secretion, ulcer development and epithelial transformation. It is known that to achieve induction of gastrin (GAS) gene expression and subsequently secretion, the inhibitory effects exerted on GAS-expressing enteroendocrine cells must be suppressed. Somatostatin (SOM) is the most effective physiologic suppressor of GAS expression. More recently, studies have revealed that menin, a tumor suppresor and gene product of the MEN1 locus, is also a strong repressor of gastrin gene expression. The OVERALL GOAL of the proposed studies is to understand the role of menin in mediating the inhibitory effect of SOM on GAS gene expression.
Three SPECIFIC AIMS are proposed: 1) To determine how somatostatin inhibits gastrin through regulation of menin; 2) To determine how menin inhibits AP1 induction of gastrin gene expression; 3) To determine how the genetic deletion of menin induces gastrin in vivo. The central hypothesis to be tested is whether there is crosstalk between the SOM inhibitory pathway and the repression induced by menin. SOM blocks cAMP generation inhibiting protein kinase A (PKA) so, we will first examine whether PKA activation must be suppressed to induce menin. A mechanism by which menin mediates its transcriptional control is through direct binding to the AP1 family member JunD. Therefore we mapped the AP1 regulatory element to the proximal gastrin promoter by deletion analysis and site-directed mutagenesis. Surprisingly, the AP1 induction required two proximal Sp1 elements. These are the same elements shown previously to mediate EGF induction of the gastrin promoter. Since AP1 family members directly bind Sp1 at its basic domain and are induced by EGF and ERKs, we will dissect how menin modulates this interaction to suppress EGF induction of gastrin. Specifically, HDAC complexes modulated by menin and known to bind Sp1 will be analyzed. Since MEN1 gastrinomas are autosomal dominant GAS-expressing tumors primarily of the duodenum, a gastrinoma mouse model will be generated by conditional gene targeting so as to study the transcriptional control of GAS in this tumor compared to physiologic GAS regulation in SOM null mice. Relevance to PUBLIC HEALTH include furthering our understanding of peptic ulcer disease, neuroendocrine transformation and the molecular basis underlying the effects of SOM analogs used to treat neuroendocrine disorders ? ? ?
| Wang, Zhen; Ocadiz-Ruiz, Ramon; Sundaresan, Sinju et al. (2018) Isolation of Enteric Glial Cells from the Submucosa and Lamina Propria of the Adult Mouse. J Vis Exp : |
| Sundaresan, Sinju; Kang, Anthony J; Merchant, Juanita L (2017) Pathophysiology of Gastric NETs: Role of Gastrin and Menin. Curr Gastroenterol Rep 19:32 |
| Sundaresan, Sinju; Kang, Anthony J; Hayes, Michael M et al. (2017) Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids. Gut 66:1012-1021 |
| Sahoo, Nirakar; Gu, Mingxue; Zhang, Xiaoli et al. (2017) Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca2+ Efflux Channel in the Tubulovesicle. Dev Cell 41:262-273.e6 |
| Sundaresan, Sinju; Meininger, Cameron A; Kang, Anthony J et al. (2017) Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells. Gastroenterology 153:1555-1567.e15 |
| Saqui-Salces, Milena; Tsao, Amy C; Gillilland 3rd, Merritt G et al. (2017) Weight gain in mice on a high caloric diet and chronically treated with omeprazole depends on sex and genetic background. Am J Physiol Gastrointest Liver Physiol 312:G15-G23 |
| Huang, Jing; Gurung, Buddha; Wan, Bingbing et al. (2012) The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482:542-6 |
| Saqui-Salces, Milena; Covés-Datson, Evelyn; Veniaminova, Natalia A et al. (2012) Inflammation and Gli2 suppress gastrin gene expression in a murine model of antral hyperplasia. PLoS One 7:e48039 |
| Berndt, Bradford E; Zhang, Min; Owyang, Stephanie Y et al. (2012) Butyrate increases IL-23 production by stimulated dendritic cells. Am J Physiol Gastrointest Liver Physiol 303:G1384-92 |
| Saqui-Salces, Milena; Dowdle, William E; Reiter, Jeremy F et al. (2012) A high-fat diet regulates gastrin and acid secretion through primary cilia. FASEB J 26:3127-39 |
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