NADPH Oxidase 1 Modulates WNT and NOTCH1 Signaling To Control the Fate of Proliferative Progenitor Cells in the Colon
Nicolas Coant,Sanae Ben Mkaddem,Sanae Ben Mkaddem,Eric Pedruzzi,Eric Pedruzzi,Cécile Guichard,Cécile Guichard,Xavier Treton,Xavier Treton,Robert Ducroc,Robert Ducroc,Jean-Noël Freund,Dominique Cazals-Hatem,Yoram Bouhnik,Yoram Bouhnik,Paul-Louis Woerther,David Skurnik,Alain Grodet,Alain Grodet,Michèle Fay,Michèle Fay,Denis Biard,Thécla Lesuffleur,Christine Deffert,Richard Moreau,Richard Moreau,André Groyer,André Groyer,Karl-Heinz Krause,Fanny Daniel,Fanny Daniel,Eric Ogier-Denis,Eric Ogier-Denis +32 more
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TLDR
It is concluded that NADPH oxidase 1 controls the balance between goblet and absorptive cell types in the colon by coordinately modulating PI3K/AKT/Wnt/β-catenin and Notch1 signaling.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.read more
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Cellular mechanisms and physiological consequences of redox-dependent signalling
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Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox‐mediated generation of reactive oxygen species
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References
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Journal ArticleDOI
The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Karen Bedard,Karl-Heinz Krause +1 more
TL;DR: This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.
Journal ArticleDOI
Control of β-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism
Chunming Liu,Yiming Li,Mikhail V. Semenov,Chun Han,Gyeong Hun Baeg,Yi Tan,Zhuohua Zhang,Xinhua Lin,Xi He +8 more
TL;DR: This study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CKIalpha as a component in Wnt/beta- catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.
Journal ArticleDOI
Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4.
Vladimir Korinek,Nick Barker,Petra Moerer,E van Donselaar,Gerwin Huls,Peter J. Peters,Hans Clevers +6 more
TL;DR: The role of Tcf-4 in colon cancer was investigated in this paper, where the authors found that Tcf7/2//- mice die shortly after birth from colon cancer.
Journal ArticleDOI
Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells.
Johan H. van Es,Marielle E. van Gijn,Orbicia Riccio,Maaike van den Born,Marc Vooijs,Harry Begthel,Miranda Cozijnsen,Sylvie Robine,Doug J. Winton,Freddy Radtke,Hans Clevers +10 more
TL;DR: This work shows a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J and indicates that γ-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.
Journal ArticleDOI
Cell transformation by the superoxide-generating oxidase Mox1
Young Ah Suh,Rebecca S. Arnold,Bernard Lassègue,Jing Shi,Xiang Xi Xu,Dan Sorescu,Andrew B. Chung,Kathy K. Griendling,J. David Lambeth +8 more
TL;DR: The cloning of mox1 is described, which encodes a homologue of the catalytic subunit of the superoxide-generating NADPH oxidase of phagocytes, gp91phox, which is expressed in colon, prostate, uterus and vascular smooth muscle, but not in peripheral blood leukocytes.
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