Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf.
Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf.
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DOI：
10.1111/j.1474-9726.2009.00501.x
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发表时间：
2009-09
期刊：
影响因子：
7.8
通讯作者：
Blackwell TK
中科院分区：
文献类型：
--
作者：
Oliveira RP;Porter Abate J;Dilks K;Landis J;Ashraf J;Murphy CT;Blackwell TK
对模式生物的研究已经确定了深刻影响衰老的调节过程，其中许多调节对环境或代谢应激的抵抗力。In C.转录调节因子SKN-1对于氧化应激抗性是重要的，并且在多种长寿途径中起作用。SKN-1是哺乳动物Nrf蛋白的直系同源物，其诱导响应于应激的第2阶段解毒基因。2相酶防御氧自由基和共轭亲电体，这些亲电体由1相解毒酶产生，代谢亲脂性化合物。在这里，我们使用表达谱来识别在正常和应激反应条件下由SKN-1调控的基因和过程。在非应激条件下，SKN-1上调了许多参与解毒、细胞修复和其他功能的基因，并下调了一组降低应激抵抗力和寿命的基因。这些基因中的许多似乎是直接SKN-1的目标，基于其启动子中预测的SKN结合位点的存在。类金属亚砷酸钠诱导某些解毒基因组的skn-1依赖性激活，包括一些在正常条件下没有SKN-1上调的基因组。有机过氧化物还触发离散的2期基因集的诱导，但另外刺激广泛的SKN-1非依赖性应答。我们的结论是，在正常情况下，SKN-1在解毒和其他过程中具有广泛的功能，包括减少寿命的调节机制。为了应对压力，SKN-1和其他调节因子调整转录程序以应对当前的挑战。我们的研究结果揭示了SKN-1功能和全身解毒防御调节的惊人复杂性。
Summary Studies in model organisms have identified regulatory processes that profoundly influence aging, many of which modulate resistance against environmental or metabolic stresses. In C. elegans the transcription regulator SKN-1 is important for oxidative stress resistance and acts in multiple longevity pathways. SKN-1 is the ortholog of mammalian Nrf proteins, which induce Phase 2 detoxification genes in response to stress. Phase 2 enzymes defend against oxygen radicals and conjugate electrophiles that are produced by Phase 1 detoxification enzymes, which metabolize lipophilic compounds. Here we have used expression profiling to identify genes and processes that are regulated by SKN-1 under normal and stress-response conditions. Under non-stressed conditions SKN-1 upregulates numerous genes involved in detoxification, cellular repair, and other functions, and downregulates a set of genes that reduce stress resistance and lifespan. Many of these genes appear to be direct SKN-1 targets, based upon presence of predicted SKN-binding sites in their promoters. The metalloid sodium arsenite induces skn-1-dependent activation of certain detoxification gene groups, including some that were not SKN-1-upregulated under normal conditions. An organic peroxide also triggers induction of a discrete Phase 2 gene set, but additionally stimulates a broad SKN-1-independent response. We conclude that under normal conditions SKN-1 has a wide range of functions in detoxification and other processes, including modulating mechanisms that reduce lifespan. In response to stress, SKN-1 and other regulators tailor transcription programs to meet the challenge at hand. Our findings reveal striking complexity in SKN-1 functions and the regulation of systemic detoxification defenses.
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