Scientific article

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

Published inMolecular and cellular biology, vol. 30, no. 11, p. 2636-2650
Publication date2010

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.

  • Animals
  • Caco-2 Cells
  • Cadherins/metabolism
  • Cell Differentiation/physiology
  • Cell Lineage
  • Cell Proliferation
  • Colon/ cytology/physiology
  • Epithelial Cells/cytology/physiology
  • Humans
  • Intestinal Mucosa/cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multipotent Stem Cells/cytology/ physiology
  • NADH, NADPH Oxidoreductases/genetics/ metabolism
  • PTEN Phosphohydrolase/metabolism
  • Proto-Oncogene Proteins c-akt/genetics/metabolism
  • Reactive Oxygen Species/metabolism
  • Receptor, Notch1/genetics/ metabolism
  • Signal Transduction/ physiology
  • Wnt Proteins/genetics/ metabolism
  • beta Catenin/metabolism
Affiliation Not a UNIGE publication
Citation (ISO format)
COANT, Nicolas et al. NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon. In: Molecular and cellular biology, 2010, vol. 30, n° 11, p. 2636–2650. doi: 10.1128/MCB.01194-09
Updates (1)
ISSN of the journal0270-7306

Technical informations

Creation08/27/2010 1:34:16 PM
First validation08/27/2010 1:34:16 PM
Update time03/14/2023 4:03:02 PM
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