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NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon

Coant, Nicolas
Ben Mkaddem, Sanae
Pedruzzi, Eric
Treton, Xavier
Ducroc, Robert
Freund, J. N.
Cazals-Hatem, Dominique
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Published in Molecular and Cellular Biology. 2010, vol. 30, no. 11, p. 2636-2650
Abstract The homeostatic self-renewal of the colonic epithelium requires coordinated regulation of the canonical Wnt/beta-catenin and Notch signaling pathways to control proliferation and lineage commitment of multipotent stem cells. However, the molecular mechanisms by which the Wnt/beta-catenin and Notch1 pathways interplay in controlling cell proliferation and fate in the colon are poorly understood. Here we show that NADPH oxidase 1 (NOX1), a reactive oxygen species (ROS)-producing oxidase that is highly expressed in colonic epithelial cells, is a pivotal determinant of cell proliferation and fate that integrates Wnt/beta-catenin and Notch1 signals. NOX1-deficient mice reveal a massive conversion of progenitor cells into postmitotic goblet cells at the cost of colonocytes due to the concerted repression of phosphatidylinositol 3-kinase (PI3K)/AKT/Wnt/beta-catenin and Notch1 signaling. This conversion correlates with the following: (i) the redox-dependent activation of the dual phosphatase PTEN, causing the inactivation of the Wnt pathway effector beta-catenin, and (ii) the downregulation of Notch1 signaling that provokes derepression of mouse atonal homolog 1 (Math1) expression. We conclude that NOX1 controls the balance between goblet and absorptive cell types in the colon by coordinately modulating PI3K/AKT/Wnt/beta-catenin and Notch1 signaling. This finding provides the molecular basis for the role of NOX1 in cell proliferation and postmitotic differentiation.
Keywords AnimalsCaco-2 CellsCadherins/metabolismCell Differentiation/physiologyCell LineageCell ProliferationColon/ cytology/physiologyEpithelial Cells/cytology/physiologyHumansIntestinal Mucosa/cytologyMiceMice, Inbred C57BLMice, KnockoutMultipotent Stem Cells/cytology/ physiologyNADH, NADPH Oxidoreductases/genetics/ metabolismPTEN Phosphohydrolase/metabolismProto-Oncogene Proteins c-akt/genetics/metabolismReactive Oxygen Species/metabolismReceptor, Notch1/genetics/ metabolismSignal Transduction/ physiologyWnt Proteins/genetics/ metabolismbeta Catenin/metabolism
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PMID: 20351171
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