Department of Biochemistry and Molecular Biology, Clark H Smith Brain Tumour Centre, Southern Alberta Cancer Research Institute, University of Calgary, HRIC, Calgary, Alberta, Canada.
EMBO J. 2012 Apr 18;31(8):1916-30. doi: 10.1038/emboj.2012.33. Epub 2012 Feb 24.
The nutrient/target-of-rapamycin (TOR) pathway has emerged as a key regulator of tissue and organismal growth in metazoans. The signalling components of the nutrient/TOR pathway are well defined; however, the downstream effectors are less understood. Here, we show that the control of RNA polymerase (Pol) III-dependent transcription is an essential target of TOR in Drosophila. We find that TOR activity controls Pol III in growing larvae via inhibition of the repressor Maf1 and, in part, via the transcription factor Drosophila Myc (dMyc). Moreover, we show that loss of the Pol III factor, Brf, leads to reduced tissue and organismal growth and prevents TOR-induced cellular growth. TOR activity in the larval fat body, a tissue equivalent to vertebrate fat or liver, couples nutrition to insulin release from the brain. Accordingly, we find that fat-specific loss of Brf phenocopies nutrient limitation and TOR inhibition, leading to decreased systemic insulin signalling and reduced organismal growth. Thus, stimulation of Pol III is a key downstream effector of TOR in the control of cellular and systemic growth.
营养物/雷帕霉素靶蛋白（TOR）途径已成为后生动物组织和机体生长的关键调节剂。营养物/TOR 途径的信号成分已经得到很好的定义；然而，下游效应物的了解较少。在这里，我们表明 RNA 聚合酶（Pol）III 依赖性转录的控制是果蝇中 TOR 的一个重要靶标。我们发现 TOR 活性通过抑制抑制剂 Maf1 并部分通过转录因子 Drosophila Myc（dMyc）来控制生长幼虫中的 Pol III。此外，我们表明 Pol III 因子 Brf 的缺失会导致组织和机体生长减少，并阻止 TOR 诱导的细胞生长。幼虫脂肪体（与脊椎动物的脂肪或肝脏相当的组织）中的 TOR 活性将营养物质与大脑中胰岛素的释放联系起来。因此，我们发现脂肪特异性 Brf 的缺失模拟了营养限制和 TOR 抑制，导致全身胰岛素信号降低和机体生长减少。因此，Pol III 的刺激是 TOR 控制细胞和全身生长的关键下游效应物。
