title: 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.
authors.affiliation: INSERM, U773, Centre de Recherche Bichat Beaujon, CRB3, BP 416, 16 rue Henri Huchard, Paris 75018, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coant
authors.forename: Sanae
authors.initials: S
authors.lastname: Ben Mkaddem
authors.forename: Eric
authors.initials: E
authors.lastname: Pedruzzi
authors.forename: Cécile
authors.initials: C
authors.lastname: Guichard
authors.forename: Xavier
authors.initials: X
authors.lastname: Tréton
authors.forename: Robert
authors.initials: R
authors.lastname: Ducroc
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Freund
authors.forename: Dominique
authors.initials: D
authors.lastname: Cazals-Hatem
authors.forename: Yoram
authors.initials: Y
authors.lastname: Bouhnik
authors.forename: Paul-Louis
authors.initials: PL
authors.lastname: Woerther
authors.forename: David
authors.initials: D
authors.lastname: Skurnik
authors.forename: Alain
authors.initials: A
authors.lastname: Grodet
authors.forename: Michèle
authors.initials: M
authors.lastname: Fay
authors.forename: Denis
authors.initials: D
authors.lastname: Biard
authors.forename: Thécla
authors.initials: T
authors.lastname: Lesuffleur
authors.forename: Christine
authors.initials: C
authors.lastname: Deffert
authors.forename: Richard
authors.initials: R
authors.lastname: Moreau
authors.forename: André
authors.initials: A
authors.lastname: Groyer
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
authors.forename: Fanny
authors.initials: F
authors.lastname: Daniel
authors.forename: Eric
authors.initials: E
authors.lastname: Ogier-Denis
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology* / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology / Q000502:physiology*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D017382:Reactive Oxygen Species; D051881:Receptor, Notch1; D051153:Wnt Proteins; D051176:beta Catenin; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase