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

Authors
  • Coant, Nicolas1
  • Ben Mkaddem, Sanae
  • Pedruzzi, Eric
  • Guichard, Cécile
  • Tréton, Xavier
  • Ducroc, Robert
  • Freund, Jean-Noel
  • Cazals-Hatem, Dominique
  • Bouhnik, Yoram
  • Woerther, Paul-Louis
  • Skurnik, David
  • Grodet, Alain
  • Fay, Michèle
  • Biard, Denis
  • Lesuffleur, Thécla
  • Deffert, Christine
  • Moreau, Richard
  • Groyer, André
  • Krause, Karl-Heinz
  • Daniel, Fanny
  • And 1 more
  • 1 INSERM, U773, Centre de Recherche Bichat Beaujon, CRB3, BP 416, 16 rue Henri Huchard, Paris 75018, France. , (France)
Type
Published Article
Journal
Molecular and Cellular Biology
Publisher
American Society for Microbiology
Publication Date
Jun 01, 2010
Volume
30
Issue
11
Pages
2636–2650
Identifiers
DOI: 10.1128/MCB.01194-09
PMID: 20351171
Source
Medline
License
Unknown

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.

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