Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling
Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling
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DOI：
10.1038/88850
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发表时间：
2001-06-01
期刊：
影响因子：
30.8
通讯作者：
Kenyon, C
中科院分区：
文献类型：
--
作者：
Lin, K;Hsin, H;Kenyon, C
秀丽隐杆线虫的寿命受胰岛素/胰岛素样生长因子(IGF)-1受体同系物DAF-2的调节，DAF-2通过保守的磷脂酰肌醇3-激酶(PI 3-K)/Akt途径(1-7)传递信号。该途径中的突变体保持年轻和活跃的时间比正常动物长得多，寿命可以延长一倍以上，这种寿命的延长需要DAF-16，一种叉头/翼状螺旋转录因子(8，9)。DAF-16被认为是DAF-2途径的主要靶点。胰岛素/IGF-1信号被认为通过AKT活性导致DAF-16的磷酸化，进而缩短寿命。在这里，我们表明，DAF-2途径防止DAF-16在细胞核中积聚。破坏DAF-16上的Akt-Consensus磷酸化位点会导致野生型动物的核积累，但令人惊讶的是，对寿命几乎没有影响。因此，DAF-2途径必须有额外的输出。线虫的寿命可以通过干扰感觉神经元或生殖细胞来延长(10，11)。在这两种情况下，延长寿命都需要DAF-16。我们发现感觉神经元和生殖系活动都调节DAF-16在细胞核内的积聚，但核定位模式不同。总而言之，这些发现揭示了DAF-16依赖的调节衰老的通路的意外复杂性。
The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway(1-7) Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long, This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor(8,9). DAF-16 is thought to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is thought to lead to phosphorylation of DAF-16 by AKT activity, which in turn shortens lifespan. Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei. Disrupting Akt-consensus phosphorylation sites in DAF-16 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outputs. Lifespan in C. elegans can be extended by perturbing sensory neurons or germ cells(10,11). In both cases, lifespan extension requires DAF-16. We find that both sensory neurons and germline activity regulate DAF-16 accumulation in nuclei, but the nuclear localization patterns are different. Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging.