NADPH Oxidase 1 Modulates WNT and NOTCH1 Signaling To Control the Fate of Proliferative Progenitor Cells in the Colon
- 1 June 2010
- journal article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 30 (11), 2636-2650
- https://doi.org/10.1128/mcb.01194-09
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
This publication has 66 references indexed in Scilit:
- Nox enzymes and oxidative stress in the immunopathology of the gastrointestinal tractSeminars in Immunopathology, 2008
- Nox1 is over‐expressed in human colon cancers and correlates with activating mutations in K‐RasInternational Journal of Cancer, 2008
- Suppressing PTEN Activity by Tobacco Smoke Plus Interleukin-1β Modulates Dissociation of VE-Cadherin/β-Catenin Complexes in EndotheliumArteriosclerosis, Thrombosis, and Vascular Biology, 2008
- Current View: Intestinal Stem Cells and SignalingGastroenterology, 2008
- Regulation of NOX1 expression by GATA, HNF-1α, and Cdx transcription factorsFree Radical Biology & Medicine, 2008
- Self-Renewal and Cancer of the Gut: Two Sides of a CoinScience, 2005
- Overexpression of a novel superoxide-producing enzyme, NADPH oxidase 1, in adenoma and well differentiated adenocarcinoma of the human colonCancer Letters, 2004
- The Tumor Suppressor PTEN Is Phosphorylated by the Protein Kinase CK2 at Its C Terminus: IMPLICATIONS FOR PTEN STABILITY TO PROTEASOME-MEDIATED DEGRADATIONJournal of Biological Chemistry, 2001
- NADPH oxidase subunit, gp91phox homologue, preferentially expressed in human colon epithelial cellsGene, 2000
- Control of endodermal endocrine development by Hes-1Nature Genetics, 2000