The Tumor Suppressor p53 Fine-Tunes Reactive Oxygen Species Levels and Neurogenesis via PI3 Kinase Signaling
The Tumor Suppressor p53 Fine-Tunes Reactive Oxygen Species Levels and Neurogenesis via PI3 Kinase Signaling
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DOI：
10.1523/jneurosci.1056-13.2013
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发表时间：
2013-09-04
影响因子：
5.3
通讯作者：
Di Giovanni, Simone
中科院分区：
文献类型：
--
作者：
Forsberg, Kirsi;Wuttke, Anja;Di Giovanni, Simone
越来越多的证据表明，内源性活性氧（ROS）在细胞信号传导中起着重要作用，包括控制细胞增殖、分化和命运。然而，ROS在胚胎小鼠神经祖细胞（eNPCs）中的功能及其分子调控尚不清楚。在这里，我们描述了生理ROS是体内和培养的NPCs发育中的端脑神经发生的适当时机所必需的，并且肿瘤抑制因子p53在ROS依赖性神经发生的调节中起关键作用。p53功能丧失导致ROS升高和早期神经发生，而p53的恢复和抗氧化处理部分逆转了与过早神经发生相关的表型。此外，我们描述了许多神经源性和氧化应激基因的表达依赖于p53， p53和ros依赖的神经发生诱导都依赖于PI3激酶/磷酸化akt信号传导。我们的研究结果表明，p53微调内源性ROS水平，以确保eNPCs中神经发生的适当时机。这也可能对神经发育起源的肿瘤的产生有影响。
Mounting evidence points to a role for endogenous reactive oxygen species (ROS) in cell signaling, including in the control of cell proliferation, differentiation, and fate. However, the function of ROS and their molecular regulation in embryonic mouse neural progenitor cells (eNPCs) has not yet been clarified. Here, we describe that physiological ROS are required for appropriate timing of neurogenesis in the developing telencephalon in vivo and in cultured NPCs, and that the tumor suppressor p53 plays a key role in the regulation of ROS-dependent neurogenesis. p53 loss of function leads to elevated ROS and early neurogenesis, while restoration of p53 and antioxidant treatment partially reverse the phenotype associated with premature neurogenesis. Furthermore, we describe that the expression of a number of neurogenic and oxidative stress genes relies on p53 and that both p53 and ROS-dependent induction of neurogenesis depend on PI3 kinase/phospho-Akt signaling. Our results suggest that p53 fine-tunes endogenous ROS levels to ensure the appropriate timing of neurogenesis in eNPCs. This may also have implications for the generation of tumors of neurodevelopmental origin.