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Deregulation of the Wnt/APC/β-catenin signaling pathway is an important consequence of tumor suppressor APC dysfunction. Genetic and molecular data have established that disruption of this pathway contributes to the development of colorectal cancer. Here, we demonstrate that the transcriptional coregulator RIP140 regulates intestinal homeostasis and tumorigenesis. Using Rip140-nuU mice and mice overexpressing human RIP140, we found that RIP140 inhibited intestinal epithelial cell proliferation and apoptosis. Interestingly, following whole-body irradiation, mice lacking RIP140 exhibited improved regenerative capacity in the intestine, while mice overexpressing RIP140 displayed reduced recovery. Enhanced RIP140 expression strongly repressed human colon cancer cell proliferation in vitro and after grafting onto nude mice. Moreover, in murine tissues and human cancer cells, RIP140 stimulated APC transcription and inhibited β-catenin activation and target gene expression. Finally, RIP140 mRNA and RIP140 protein levels were decreased in human colon cancers compared with those in normal mucosal tissue, and low levels of RIP140 expression in adenocarcinomas from patients correlated with poor prognosis. Together, these results support a tumor suppressor role for RIP140 in colon cancer., Introduction The Wnt pathway is one of the major pathways deregulated in colorectal cancer. In the physiologically normal gut, activation of this pathway ensures proliferation of precursor cells and renewal [...]

In the stomach, strictly regulated cell adherens junctions are crucial in determining epithelial cell differentiation. Sonic Hedgehog (Shh) regulates epithelial cell differentiation in the adult stomach. We sought to identify whether Shh plays a role in regulating adherens junction protein E-cadherin as a mechanism for epithelial cell differentiation. Mouse nontumorigenic gastric epithelial (IMGE-5) cells treated with Hedgehog signaling inhibitor cyclopamine and anti-Shh 5El antibody or transduced with short hairpin RNA against Skinny Hedgehog ([IMGE-5.sup.Ski]) were cultured. A mouse model expressing a parietal cell-specific deletion of Shh (HKCre/[Shh.sup.KO]) was used to identify further changes in adherens and tight junctions. Inhibition of Hedgehog signaling in IMGE-5 cells caused loss of E-cadherin expression accompanied by disruption of F-actin cortical expression and relocalization of zonula occludens-1 (ZO-1). Loss of E-cadherin was also associated with increased proliferation in [IMGE-5.sup.Ski] cells and increased expression of the mucous neck cell lineage marker MUC6. Compared with membrane-expressed E-cadherin and ZO-1 protein in controls, dissociation of E-cadherin/[beta]-catenin and ZO-1/occludin protein complexes was observed in HKCre/[Shh.sup.KO] mice. In conclusion, we demonstrate that Hedgehog signaling regulates E-cadherin expression that is required for the maintenance of F-actin cortical expression and stability of tight junction protein ZO-1. IMGE-5 cells; epithelial-to-mesenchymal-transition, zonula occludens-1 doi: 10.1152/ajpgi.00512.2009.

The role of gastrin in histamine synthesis in enterochromaffin-like cells isolated from the rabbit fundic mucosa was investigated. The number of histidine decarboxylase molecules was measured as a function of histamine release and activity. Data on the kinetic parameters of this enzyme suggested the involvement of 'gastrin/CCK-B type' receptors coupled with a PTX-sensitive G protein in the regulation of histamine synthesis by gastrin.

Studies on isolated rabbit fundic mucosal cells reveal that gastrin and cholecystokinin octapeptide enhance histamine synthesis by interacting with a receptor present on enterochromaffin-like cells. The muscarinic agonists can also stimulate histidine decarboxylase (HDC) activity by interacting with muM1 receptor. Gastrin and carbachol enhance HDC affinity for L-histidine.

An analysis of histamine-regulated histidine decarboxylase activity in samples of rabbit gastric mucosal cells, incorporated with mucous and endocrine cells, revealed the role of histamine during negative regulation of histamine synthesis. This downregulation involves a pathway featuring induction of autoreceptors which possess pharmacological properties, similar to those of H3 receptors. Mucosal cells, pre-treated with thioperamide, released large quantities of histamine during experiments performed on fraction F1 population of histamine-secreting cells from rabbit gastric mucosa.

HGF regulates tight junctions in new nontumorigenic gastric epithelial cell line. Am J Physiol Gastrointest Liver Physiol 280: G910-G921, 2001.--The regulation of intercellular adhesion by hepatocyte growth factor (HGF) was examined on a novel nontumorigenic gastric epithelial cell line (IMGE-5) derived from H-2Kb-tsA58 transgenic mice. IMGE-5 cells constitutively expressed cytokeratin 18 and HGF receptors. Under permissive conditions (33 [degrees] C + interferon-[Gamma]), IMGE-5 cells proliferated rapidly but did not display membrane expression of adherens and tight junction proteins. Under nonpermissire conditions, their proliferation was decreased and they displayed a strong, localized membrane expression of E-cadherin/[Beta]-catenin and occludin/ZO-1. HGF treatment largely prevented the targeting of ZO-1 to the tight junction and induced a significant decrease of the transepithelial resistance measured across a confluent IMGE-5 cell monolayer. HGF rapidly increased the tyrosine phosphorylation of ZO-1 and decreased its association with occludin in a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent manner. PI 3-kinase was also involved in HGF-induced migration of IMGE-5 cells. Our results demonstrate that 1) HGF prevents the appearance of ZO-1 in the membrane during epithelial cell differentiation; 2) HGF causes partial relocalization of ZO-1 to the cytoplasm and nucleus and concomitantly stimulates cell dissociation and migration; and 3) IMGE-5 cells offer a useful model for the study of gastric epithelial cell differentiation. hepatocyte growth factor; ZO-1; occludin; gastric epithelial cell line; ImmortoMouse

In the stomach, strictly regulated cell adherens junctions are crucial in determining epithelial cell differentiation. Sonic Hedgehog (Shh) regulates epithehal cell differentiation in the adult stomach. We sought to identify whether Shh plays a role in regulating adherens junction protein E-cadherin as a mechanism for epithelial cell differentiation. Mouse nontumorigenic gastric epithelial (IMGE-5) cells treated with Hedgehog signaling inhibitor cyclopamine and anti-Shh 5E1 antibody or transduced with short hairpin RNA against Skinny Hedgehog (IMGE- 5ski) were cultured. A mouse model expressing a parietal cell-specific deletion of Shh (HKCre/ShhKO) was used to identify further changes in adherens and tight junctions. Inhibition of Hedgehog signaling in IMGE-5 cells caused loss of E-cadherin expression accompanied by disruption of F-actin cortical expression and relocalization of zonula occludens-1 (ZO-1). Loss of E-cadherin was also associated with increased proliferation in IMGE-5ski cells and increased expression of the mucous neck cell lineage marker MUC6. Compared with membrane-expressed E-cadherin and ZO- 1 protein in controls, dissociation of E-cadherin/β-catenin and ZO-1/occludin protein complexes was observed in HKCre/ShhKO mice. In conclusion, we demonstrate that Hedgehog signaling regulates E-cadherin expression that is required for the maintenance of F-actin cortical expression and stability of tight junction protein ZO-1. [ABSTRACT FROM AUTHOR]