Department of Physiological Chemistry, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht, The Netherlands.
Antioxid Redox Signal. 2011 Mar 15;14(6):1093-106. doi: 10.1089/ars.2010.3403. Epub 2010 Sep 20.
The forkhead box O (FOXO) family of transcription factors regulates a variety of cellular programs, including cell cycle arrest, reactive oxygen species (ROS) scavenging, and apoptosis, and are of key importance in the decision over cell fate. In animal model systems it has been shown that FOXO is involved in the regulation of long lifespan. FOXO activity is tightly controlled by the insulin signaling pathway and by a multitude of ROS-induced posttranslational modifications. In the cell, ROS levels can be sensed by virtue of stimulatory and inhibitory oxidative modification of cysteine residues within proteins that control various signaling cascades. Recently, it was shown that cysteines in FOXO can also act as sensors of the local redox state. In this review we have outlined the cysteine-dependent redox switches that regulate both the insulin and ROS signaling pathways upstream of FOXO. Further, we describe how FOXO controls ROS levels by transcriptional regulation of a multilayered antioxidant system. Finally, we will discuss how cysteine-based redox signaling to FOXO could play a role in fine-tuning the optimal cellular response to ROS to control organismal lifespan.
叉头框 O (FOXO) 转录因子家族调节多种细胞程序，包括细胞周期停滞、活性氧 (ROS) 清除和细胞凋亡，在细胞命运的决定中至关重要。在动物模型系统中已经表明，FOXO 参与了长寿的调节。FOXO 的活性受到胰岛素信号通路和多种 ROS 诱导的翻译后修饰的严格控制。在细胞中，ROS 水平可以通过刺激和抑制控制各种信号级联的蛋白质中半胱氨酸残基的氧化修饰来感知。最近，已经表明 FOXO 中的半胱氨酸也可以作为局部氧化还原状态的传感器。在这篇综述中，我们概述了调节 FOXO 上游胰岛素和 ROS 信号通路的依赖半胱氨酸的氧化还原开关。此外，我们描述了 FOXO 如何通过转录调节多层次抗氧化系统来控制 ROS 水平。最后，我们将讨论基于半胱氨酸的氧化还原信号传递到 FOXO 如何在微调细胞对 ROS 的最佳反应以控制生物体寿命方面发挥作用。
