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

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.

DOI: 10.1128/MCB.01194-09
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@article{Coant2010NADPHO1, title={NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon.}, author={Nicolas Coant and Sanae Ben Mkaddem and Eric P{\'e}druzzi and C{\'e}cile Guichard and Xavier Tr{\'e}ton and Robert A Ducroc and Jean-Noel Freund and Dominique Cazals-Hatem and Yoram Bouhnik and Paul-Louis Woerther and David Skurnik and Alain Grodet and Mich{\`e}le Fay and Denis Biard and Th{\'e}cla Lesuffleur and Christine Deffert and Richard Moreau and Andr{\'e} Groyer and K Krause and Fanny Daniel and Eric Ogier-Denis}, journal={Molecular and cellular biology}, year={2010}, volume={30 11}, pages={2636-50} }