Expression of Drosophila FOXO regulates growth and can phenocopy starvation.
Expression of Drosophila FOXO regulates growth and can phenocopy starvation.
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DOI：
10.1186/1471-213x-3-5
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发表时间：
2003-07-05
影响因子：
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通讯作者：
Staveley, Brian E
中科院分区：
文献类型：
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作者：
Kramer, Jamie M;Davidge, Jason T;Staveley, Brian E
背景：胰岛素信号通路的组分是重要的生长调节剂。FOXO（叉头框，亚组“0”）转录因子在低水平胰岛素信号传导的条件下调节细胞过程。在哺乳动物细胞培养中的研究表明，FOXO转录因子的激活导致细胞死亡或细胞周期停滞。秀丽隐杆线虫同源FOXO，Daf-16，是需要的dauer幼虫的形成，以响应营养胁迫。此外，FOXO因子已牵连在抗应激和longevision.Results：我们已经确定了果蝇同源FOXO（dFOXO），这是保守的氨基酸序列相比，哺乳动物FOXO同源物和Daf-16。dFOXO在早期幼虫发育过程中的表达导致幼虫生长抑制和摄食行为的改变。dFOXO表达停止后，幼虫生长的抑制是可逆的。在第三龄幼虫期间或在发育期间以低水平表达dFOXO导致产生尺寸减小的成虫。对这些小苍蝇的翅膀和眼睛的分析表明，大小的减少是由于细胞大小和细胞数量的减少。dFOXO在发育中的眼睛中的过表达导致细胞大小和细胞数量减少的特征性表型。这种表型可以获救的上游胰岛素信号传导组件，dPI 3 K和dAkt的共表达，然而，这种救援是没有看到当FOXO突变成组成型活性form.CONCLUSIONS：dFOXO是保守的序列和监管机制相比，与其他FOXO同源物。果蝇作为研究FOXO转录因子的模型的建立应该证明有利于确定这些信号分子的生物学作用。过表达dFOXO后观察到的幼虫发育的改变密切模仿饥饿的表型效应，表明dFOXO在响应营养逆境中的作用。这项工作对理解癌症和胰岛素相关疾病（如糖尿病和肥胖症）具有重要意义。
BACKGROUND: Components of the insulin signaling pathway are important regulators of growth. The FOXO (forkhead box, sub-group "O") transcription factors regulate cellular processes under conditions of low levels of insulin signaling. Studies in mammalian cell culture show that activation of FOXO transcription factors causes cell death or cell cycle arrest. The Caenorhabditis elegans homologue of FOXO, Daf-16, is required for the formation of dauer larvae in response to nutritional stress. In addition, FOXO factors have been implicated in stress resistance and longevity.RESULTS: We have identified the Drosophila melanogaster homologue of FOXO (dFOXO), which is conserved in amino acid sequence compared with the mammalian FOXO homologues and Daf-16. Expression of dFOXO during early larval development causes inhibition of larval growth and alterations in feeding behavior. Inhibition of larval growth is reversible upon discontinuation of dFOXO expression. Expression of dFOXO during the third larval instar or at low levels during development leads to the generation of adults that are reduced in size. Analysis of the wings and eyes of these small flies indicates that the reduction in size is due to decreases in cell size and cell number. Overexpression of dFOXO in the developing eye leads to a characteristic phenotype with reductions in cell size and cell number. This phenotype can be rescued by co-expression of upstream insulin signaling components, dPI3K and dAkt, however, this rescue is not seen when FOXO is mutated to a constitutively active form.CONCLUSIONS: dFOXO is conserved in both sequence and regulatory mechanisms when compared with other FOXO homologues. The establishment of Drosophila as a model for the study of FOXO transcription factors should prove beneficial to determining the biological role of these signaling molecules. The alterations in larval development seen upon overexpression of dFOXO closely mimic the phenotypic effects of starvation, suggesting a role for dFOXO in the response to nutritional adversity. This work has implications in the understanding of cancer and insulin related disorders, such as diabetes and obesity.