NADPH Oxidase 1 Modulates WNT and NOTCH1 Signaling To Control the Fate of Proliferative Progenitor Cells in the Colon
NADPH Oxidase 1 Modulates WNT and NOTCH1 Signaling To Control the Fate of Proliferative Progenitor Cells in the Colon
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DOI：
10.1128/mcb.01194-09
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发表时间：
2010-06-01
影响因子：
5.3
通讯作者：
Ogier-Denis, Eric
中科院分区：
文献类型：
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作者：
Coant, Nicolas;Ben Mkaddem, Sanae;Ogier-Denis, Eric
结肠上皮的稳态自我更新需要经典Wnt/β-连环蛋白和Notch信号通路的协调调节，以控制多能干细胞的增殖和谱系定型。然而，Wnt/β-连环蛋白和Notch 1通路在控制结肠中细胞增殖和命运中相互作用的分子机制知之甚少。在这里，我们表明，NADPH氧化酶1（NOX 1），活性氧（ROS）产生的氧化酶，在结肠上皮细胞中高度表达，是一个关键的决定因素，细胞增殖和命运，整合Wnt/β-连环蛋白和Notch 1信号。NOX 1缺陷小鼠显示，由于磷脂酰肌醇3-激酶（PI 3 K）/AKT/Wnt/β-连环蛋白和Notch 1信号转导的协同抑制，祖细胞大量转化为有丝分裂后杯状细胞，代价是结肠细胞。这种转化与以下相关：（i）双重磷酸酶PTEN的氧化还原依赖性激活，导致Wnt途径效应物β-连环蛋白的失活，以及（ii）Notch 1信号转导的下调，引起小鼠无调同源物1（Math 1）表达的去抑制。我们的结论是，NOX 1通过协调调节PI 3 K/AKT/Wnt/β-catenin和Notch 1信号转导来控制结肠中杯状细胞和吸收细胞类型之间的平衡。这一发现为NOX 1在细胞增殖和有丝分裂后分化中的作用提供了分子基础。
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.