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- W2988585412 abstract "1011 Development of colon cancer is driven by alterations in intestinal cell maturation, and therefore understanding mechanisms that regulate the balance among different cell lineages is critical to understanding intestinal tumorigenesis. Here, through isolation of intestinal epithelial cells as a function of their position along the crypt-villus axis (CVA), we report that active canonical Notch/Hes1 signaling in vivo marks the uncommitted, proliferative cells in the small intestine of the mouse, with Math1 showing complementary up-regulation as cells migrate along the CVA towards the intestinal lumen. Consistent with this pattern of in vivo expression, HES1 was down-regulated in both Caco-2 and HT29 Cl16E human colon carcinoma cell lines in culture during their spontaneous differentiation along the enterocyte and goblet cell lineages, respectively. In HT29 Cl16E cells, impaired activation of Notch receptors by treatment with 10 μM gamma-secretase led to cell cycle arrest at G1 and p21 promoter activation, and concomitant induction of expression of the MUC2 and TFF3 goblet cell markers. Conversely, the co-culture of HT29 Cl16E cells with mouse L fibroblasts engineered to express the Delta1 ligand, as well as infection with an adenovirus that expressed a constitutively active Notch1 receptor, repressed the expression of HATH1, MUC2 and TFF3 at the mRNA and protein levels. This effect was mediated by HATH1 since its targeted knock-down by specific siRNAs also inhibited MUC2 and TFF3 expression. Surprisingly, in Caco2 cells, the Notch/Hes1 signaling pathway also repressed enterocyte differentiation, as indicated by inhibition of alkaline phosphatase, sucrase isomaltase and liver fatty acid binding protein expression, all enterocyte specific markers. Of interest, HATH1 expression level was higher in HT29 Cl16E goblet-like cells than in Caco-2 absorptive cells and its transcripts were repressed upon sodium butyrate treatment, a physiological inducer of cell cycle arrest and absorptive cell differentiation. Our results suggest that Notch signaling is required to maintain both intestinal cell progenitors and colon cancer cells in a highly proliferative state, and provide novel insight into the molecular mechanisms involved in intestinal cell fate specification induced by Notch signaling, both key to the maintenance of mucosal homeostasis." @default.
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- W2988585412 date "2007-05-01" @default.
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- W2988585412 title "Canonical Notch signaling functions as a commitment switch for intestinal epithelial cells." @default.
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