The search for DAF-16/FOXO transcriptional targets: Approaches and discoveries
The search for DAF-16/FOXO transcriptional targets: Approaches and discoveries
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DOI：
10.1016/j.exger.2006.06.040
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发表时间：
2006-10-01
影响因子：
3.9
通讯作者：
Murphy, Coleen T.
中科院分区：
文献类型：
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作者：
Murphy, Coleen T.
胰岛素/胰岛素样生长因子-1受体(IIR)/FOXO通路在蠕虫、苍蝇和哺乳动物中非常保守，下调这一通路中的信号已被证明在所有这些动物中都能延长寿命。FOXO介导的转录是IIR突变体长寿命所必需的；因此，人们对识别FOXO靶基因非常感兴趣，因为它们可能执行延长寿命的生化活动。已有许多方法被用于确定FOXO的转录靶点。到目前为止，关于这条途径下游成分的最佳数据来自涉及秀丽线虫FOXO转录因子DAF-16的实验；其中一些靶点已经被测试它们对长寿、Dauer形成和脂肪储存的贡献。在这里，我检查和比较了用于识别DAF-16/FOXO靶标的方法，回顾了DAF-16调控的基因，并讨论了可能在延长IIR突变体寿命方面发挥作用的过程。DAF-16似乎不是上调每个可能的有益基因，而是选择性地上调有助于特定保护机制的基因，同时下调潜在的有害基因。除了在压力保护中执行预期作用的基因外，这些研究还发现了许多以前未知的靶点，这表明一些延长寿命的机制仍有待发现。这些机制可以协同作用或累积作用以延长寿命，并且在高等生物中可能至少部分保守。(C)2006 Elsevier Inc.保留所有权利。
The insulin/IGF-1 receptor (IIR)/FOXO pathway is remarkably conserved in worms, flies, and mammals, and downregulation of signaling in this pathway has been shown to extend lifespan in all of these animals. FOXO-mediated transcription is required for the long lifespan of IIR mutants; thus, there is great interest in identifying FOXO target genes, as they may carry out the biochemical activities that extend longevity. A number of approaches have been used to identify the transcriptional targets of FOXO. Thus far, the best data available on the components downstream of this pathway are from experiments involving the Caenorhabditis elegans FOXO transcription factor, DAF-16; some of these targets have been tested for their contributions to longevity, dauer formation, and fat storage. Here, I examine and compare the approaches used to identify DAF-16/FOXO targets, review the genes regulated by DAF-16, and discuss the processes that may be at work to extend lifespan in IIR mutants. Rather than upregulating every possible beneficial gene, DAF-16 appears to selectively upregulate genes that contribute to specific protective mechanisms, while simultaneously downregulating potentially deleterious genes. In addition to genes that carry out expected roles in stress protection, many previously unknown targets have been identified in these studies, suggesting that some mechanisms of lifespan extension still await discovery. These mechanisms may act cooperatively or cumulatively to increase longevity, and are likely to be at least partially conserved in higher organisms. (c) 2006 Elsevier Inc. All rights reserved.