Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm.
Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm.
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长期的饥饿和衰老诱导DAF-16/FOXO对细胞质的Age-1/Pi 3-激酶依赖性易位。
DOI：
10.1186/1741-7007-4-1
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发表时间：
2006-02-03
期刊：
影响因子：
5.4
通讯作者：
Divecha, N
中科院分区：
文献类型：
--
作者：
Weinkove, D;Halstead, JR;Gems, D;Divecha, N
提供压力抵抗力会转移用于发育和繁殖的资源，因此必须严格调控。在秀丽隐杆线虫中，通过饥饿期提高应激抗性以促进存活的开关由α-16/FOXO转录因子调节。AGE-1的功能降低突变，C. elegans IA类磷酸肌醇3-激酶（PI 3 K），以daf-16依赖性方式增加寿命和应激抗性。IA类PI 3 K通过诱导FOXO易位至细胞质来下调FOXO。然而，AGE-1在何种情况下被正常激活尚不清楚。为了解决这个问题，我们使用了C。线虫第一阶段幼虫（L1），饥饿时进入发育停滞的滞育阶段，直到遇到食物。我们发现，在L1的饥饿和daf-16是必要的，赋予抗氧化应激的形式过氧化氢。因此，在短期饥饿后，β-16定位于细胞核。然而，在长期饥饿后，α-16意外地易位到细胞质中。这种易位需要功能性年龄-1。H_2O_2处理可以复制这种易位并诱导AGE-1产物PIP 3的产生。因为在衰老的成年C.这些动物也可能经历长期的饥饿。与我们在L1中的观察结果一致，在老年蠕虫中，α-16也以1岁依赖性的方式易位到细胞质中。在饥饿的L1滞育过程中，β-16被激活。长期饥饿后，β-16向细胞质的转运可能是一种反馈机制，防止过度消耗抗逆能力。H2 O2是这种反馈机制中的候选第二信使。在age-1（hx 546）突变体中缺乏这种反应表明了一种新的机制，这种突变增加了寿命。
The provision of stress resistance diverts resources from development and reproduction and must therefore be tightly regulated. In Caenorhabditis elegans, the switch to increased stress resistance to promote survival through periods of starvation is regulated by the DAF-16/FOXO transcription factor. Reduction-of-function mutations in AGE-1, the C. elegans Class IA phosphoinositide 3-kinase (PI3K), increase lifespan and stress resistance in a daf-16 dependent manner. Class IA PI3Ks downregulate FOXOs by inducing their translocation to the cytoplasm. However, the circumstances under which AGE-1 is normally activated are unclear. To address this question we used C. elegans first stage larvae (L1s), which when starved enter a developmentally-arrested diapause stage until food is encountered. We find that in L1s both starvation and daf-16 are necessary to confer resistance to oxidative stress in the form of hydrogen peroxide. Accordingly, DAF-16 is localised to cell nuclei after short-term starvation. However, after long-term starvation, DAF-16 unexpectedly translocates to the cytoplasm. This translocation requires functional age-1. H2O2 treatment can replicate the translocation and induce generation of the AGE-1 product PIP3. Because feeding reduces to zero in ageing adult C. elegans, these animals may also undergo long-term starvation. Consistent with our observation in L1s, DAF-16 also translocates to the cytoplasm in old adult worms in an age-1-dependent manner. DAF-16 is activated in the starved L1 diapause. The translocation of DAF-16 to the cytoplasm after long-term starvation may be a feedback mechanism that prevents excessive expenditure on stress resistance. H2O2 is a candidate second messenger in this feedback mechanism. The lack of this response in age-1(hx546) mutants suggests a novel mechanism by which this mutation increases longevity.
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影响因子：
9.2
作者：
Halstead, JR;Roefs, M;Divecha, N
通讯作者：
Divecha, N
DOI：
10.1073/pnas.0400848101
发表时间：
2004-05-25
影响因子：
11.1
作者：
Huang, C;Xiong, CJ;Kornfeld, K
通讯作者：
Kornfeld, K
影响因子：
4.8
作者：
Lee, SR;Yang, KS;Rhee, SG
通讯作者：
Rhee, SG
影响因子：
7.8
作者：
McElwee, J;Bubb, K;Thomas, JH
通讯作者：
Thomas, JH
影响因子：
64.8
作者：
Morris, JZ;Tissenbaum, HA;Ruvkun, G
通讯作者：
Ruvkun, G