Caenorhabditis elegans PI3K mutants reveal novel genes underlying exceptional stress resistance and lifespan.
Caenorhabditis elegans PI3K mutants reveal novel genes underlying exceptional stress resistance and lifespan.
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DOI：
10.1111/j.1474-9726.2009.00524.x
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发表时间：
2009-12
期刊：
影响因子：
7.8
通讯作者：
Shmookler Reis RJ
中科院分区：
文献类型：
--
作者：
Ayyadevara S;Tazearslan C;Bharill P;Alla R;Siegel E;Shmookler Reis RJ
在激酶结构域之前截断i类磷脂酰肌醇3-激酶催化亚基（PI3KCS）的两个1岁无意义突变体赋予秀丽隐杆线虫非凡的寿命和抗逆性。这些特征是第二代纯合子所特有的，在第一代时变得迟钝，并且在很大程度上被DAF-16/FOXO的额外突变逆转，DAF-16/FOXO是胰岛素样信号中AGE-1下游的转录因子。将年龄1强等位基因（mg44, m333）与较弱的hx546等位基因在表达微阵列上进行比较，检测每个等位基因的4个独立队列。在276个具有显著差异表达的基因中，92%的基因在携带强烈的age-1等位基因的成年人中转录量比hx546少。这一比例明显大于将1岁等位基因与野生型蠕虫进行对比时所观察到的轻微偏差。因此，无义等位基因特有的转录变化主要涉及基因沉默或转录激活失败。在携带强或弱1岁等位基因的蠕虫中，通过实时聚合酶链反应重新评估了优先响应1岁无义等位基因的基因子集；几乎所有这些基因对age-1（mg44）等位基因的反应都明显高于对age-1（hx546）等位基因的反应。daf-16的额外突变使大多数改变的mg44- f2表达水平恢复到大约野生型的水平，尽管大量基因仍然与野生型明显不同，这意味着age-1（mg44）通过daf-16 / foxo依赖性和非依赖性通道调节转录。当RNA干扰（RNAi）在野生型或1岁（hx546）成人中靶向1岁抑制基因时，大多数具有显著的氧化应激保护作用。先前的研究显示，靶向其中两个基因的RNAi构建物可以延长寿命，而本次研究发现，靶向五个新基因的RNAi构建物可以延长寿命。因此，pi3k缺失突变可能涉及新的延长寿命机制。
Two age-1 nonsense mutants, truncating the class-I phosphatidylinositol 3-kinase catalytic subunit (PI3KCS) before its kinase domain, confer extraordinary longevity and stress-resistance to Caenorhabditis elegans. These traits, unique to second-generation homozygotes, are blunted at the first generation and are largely reversed by additional mutations to DAF-16/FOXO, a transcription factor downstream of AGE-1 in insulin-like signaling. The strong age-1 alleles (mg44, m333) were compared with the weaker hx546 allele on expression microarrays, testing four independent cohorts of each allele. Among 276 genes with significantly differential expression, 92% showed fewer transcripts in adults carrying strong age-1 alleles rather than hx546. This proportion is significantly greater than the slight bias observed when contrasting age-1 alleles to wild-type worms. Thus, transcriptional changes peculiar to nonsense alleles primarily involve either gene silencing or failure of transcriptional activation. A subset of genes responding preferentially to age-1-nonsense alleles was reassessed by real-time polymerase chain reaction, in worms bearing strong or weak age-1 alleles; nearly all of these were significantly more responsive to the age-1(mg44) allele than to age-1(hx546). Additional mutation of daf-16 reverted the majority of altered mg44-F2 expression levels to approximately wild-type values, although a substantial number of genes remained significantly distinct from wild-type, implying that age-1(mg44) modulates transcription through both DAF-16/FOXO-dependent and –independent channels. When age-1-inhibited genes were targeted by RNA interference (RNAi) in wild-type or age-1(hx546) adults, most conferred significant oxidative-stress protection. RNAi constructs targeting two of those genes were shown previously to extend life, and RNAi’s targeting five novel genes were found here to increase lifespan. PI3K-null mutants may thus implicate novel mechanisms of life extension.
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