The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C-elegans
The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C-elegans
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DOI：
10.1038/40194
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发表时间：
1997-10-30
期刊：
影响因子：
64.8
通讯作者：
Ruvkun, G
中科院分区：
文献类型：
--
作者：
Ogg, S;Paradis, S;Ruvkun, G
在哺乳动物中，胰岛素信号调节葡萄糖转运以及各种代谢酶的表达和活性。在秀丽隐杆线虫（Caenorhabditis elegans）中，一条相关通路调节着代谢、发育和寿命（1,2）。野生型动物由于分泌大量的信息素(3)而进入发育迟缓阶段，在肠道和皮下积聚大量脂肪。DAF-2（哺乳动物胰岛素受体的同源物）和AGE-1（哺乳动物磷脂酰肌醇3- oh激酶的催化亚基的同源物）的突变体在幼年阶段阻止发育(3)。此外，DAF-2和AGE-1的弱突变或温度敏感突变的动物可以繁殖，但仍然表现出增加的能量储存和寿命（1,2,4,5）。我们发现daf-16的零突变抑制daf-2或age-1突变的作用；缺乏daf-16绕过了这种胰岛素受体样信号通路的需要。因此，DAF-2/AGE-1信号的主要作用是拮抗DAF-16。daf-16广泛表达并编码叉头转录因子家族的三个成员，DAF-2途径与线虫tgf - β型信号DAF-7激活的途径协同作用，表明daf-16与线虫SMAD蛋白协同调节关键代谢和发育控制基因的转录。可能的DAF-16的人类同源物，FKHR和AFX，也可能在胰岛素信号的下游发挥作用，并与tgf - β效应物合作介导代谢调节。这些基因可能在糖尿病中失调。
In mammals, insulin signalling regulates glucose transport together with the expression and activity of various metabolic enzymes. In the nematode Caenorhabditis elegans, a related pathway regulates metabolism, development and longevity(1,2). Wild-type animals enter the developmentally arrested dauer stage in response to high levels of a secreted pheromone(3), accumulating large amounts of fat in their intestines and hypodermis. Mutants in DAF-2 (a homologue of the mammalian insulin receptor) and AGE-1 (a homologue of the catalytic subunit of mammalian phosphatidylinositol 3-OH kinase) arrest development at the dauer stage(3), Moreover, animals bearing weak or temperature-sensitive mutations in daf-2 and age-1 can develop reproductively, but nevertheless show increased energy storage and longevity(1,2,4,5). Here we show that null mutations in daf-16 suppress the effects of mutations in daf-2 or age-1; lack of daf-16 bypasses the need for this insulin receptor-like signalling pathway. The principal role of DAF-2/AGE-1 signalling is thus to antagonize DAF-16. daf-16 is widely expressed and encodes three members of the Fork head family of transcription factors, The DAF-2 pathway acts synergistically with the pathway activated by a nematode TGF-beta-type signal, DAF-7, suggesting that DAF-16 cooperates with nematode SMAD proteins in regulating the transcription of key metabolic and developmental control genes. The probable human orthologues of DAF-16, FKHR and AFX, may also act downstream of insulin signalling and cooperate with TGF-beta effecters in mediating metabolic regulation. These genes may be dysregulated in diabetes.