The Drosophila FoxA ortholog Fork head regulates growth and gene expression downstream of Target of rapamycin.
The Drosophila FoxA ortholog Fork head regulates growth and gene expression downstream of Target of rapamycin.
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DOI：
10.1371/journal.pone.0015171
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发表时间：
2010-12-31
期刊：
影响因子：
3.7
通讯作者：
Jünger MA
中科院分区：
文献类型：
--
作者：
Bülow MH;Aebersold R;Pankratz MJ;Jünger MA
FoxO亚家族的叉头转录因子调节胰岛素信号网络下游的基因表达程序。目前尚不清楚哪些蛋白质介导雷帕霉素靶蛋白（TOR）信号传导所施加的转录控制，但最近在线虫中的研究表明TOR下游的FoxA转录因子的作用。在这项研究中，我们提出的证据，概述了一个类似的连接在果蝇，其中FoxA蛋白叉头（FKH）调节TOR下游的细胞和生物体的大小。我们发现FKH在幼虫组织中的异位表达和靶向敲低导致不同大小的表型，这取决于营养状态和TOR信号水平。FKH过表达对进食条件下的生长具有负面影响，并且这种表型不会因经由雷帕霉素进食抑制TOR而进一步加剧。在饥饿或低TOR信号传导水平的条件下，FKH的敲低减弱了与这些条件相关的尺寸减小。内源性FKH蛋白的亚细胞定位从高蛋白饮食的主要细胞质转移到TOR水平降低或喂食雷帕霉素的动物中的显著核积累。两个假定的FKH靶基因，CG6770和cabut，由雷帕霉素或FKH表达转录诱导，并通过FKH敲低沉默。杂合TOR突变动物中两种靶基因的诱导均受到fkh突变的抑制。此外，TOR信号传导水平和FKH影响dFOXO靶基因d4E-BP的转录，这意味着与胰岛素途径的串扰点。总之，我们的观察结果表明，FKH水平的改变对细胞和生物体大小有影响，并且FKH功能是由低TOR信号传导水平引起的生长抑制和靶基因诱导所必需的。
Forkhead transcription factors of the FoxO subfamily regulate gene expression programs downstream of the insulin signaling network. It is less clear which proteins mediate transcriptional control exerted by Target of rapamycin (TOR) signaling, but recent studies in nematodes suggest a role for FoxA transcription factors downstream of TOR. In this study we present evidence that outlines a similar connection in Drosophila, in which the FoxA protein Fork head (FKH) regulates cellular and organismal size downstream of TOR. We find that ectopic expression and targeted knockdown of FKH in larval tissues elicits different size phenotypes depending on nutrient state and TOR signaling levels. FKH overexpression has a negative effect on growth under fed conditions, and this phenotype is not further exacerbated by inhibition of TOR via rapamycin feeding. Under conditions of starvation or low TOR signaling levels, knockdown of FKH attenuates the size reduction associated with these conditions. Subcellular localization of endogenous FKH protein is shifted from predominantly cytoplasmic on a high-protein diet to a pronounced nuclear accumulation in animals with reduced levels of TOR or fed with rapamycin. Two putative FKH target genes, CG6770 and cabut, are transcriptionally induced by rapamycin or FKH expression, and silenced by FKH knockdown. Induction of both target genes in heterozygous TOR mutant animals is suppressed by mutations in fkh. Furthermore, TOR signaling levels and FKH impact on transcription of the dFOXO target gene d4E-BP, implying a point of crosstalk with the insulin pathway. In summary, our observations show that an alteration of FKH levels has an effect on cellular and organismal size, and that FKH function is required for the growth inhibition and target gene induction caused by low TOR signaling levels.
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