Department of Biochemistry and Molecular Biology, and Clark H. Smith Brain Tumour Centre, Southern Alberta Cancer Research Institute, University of Calgary, HRIC, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Dev Biol. 2012 Nov 15;371(2):191-202. doi: 10.1016/j.ydbio.2012.08.020. Epub 2012 Aug 31.
Nutrient availability is a key determinant of animal growth. The conserved insulin/PI3 kinase and TOR kinase signaling pathways are two of the best characterized regulators of cell and tissue growth in response to nutritional conditions. Studies in Drosophila larvae show that one mechanism by which these pathways drive growth is by regulating the expression of metabolic genes, especially those genes required for protein synthesis. Here we examine a role for the transcription factor DREF in mediating some of these transcriptional and growth responses. We find that loss of DREF leads to a decrease in organismal growth. These effects are in part due to a requirement for DREF function in cell-autonomous growth. We also uncover a non-autonomous role for DREF activity in the larval fat body. Previous studies show that activation of TOR in the fat body couples nutrition to insulin release from the brain; we find that inhibition of DREF in the fat body can phenocopy effects of nutrient deprivation and fat-specific TOR inhibition, leading to a reduction in systemic insulin signaling, delayed larval growth and smaller final size. Using genetic epistasis, we find that DREF is required for growth downstream of TOR, but not insulin/PI3K signaling. Moreover, we show that TOR can control DREF mRNA levels, in part via the transcription factor dMyc. Finally we show that DREF is required for normal expression of many ribosome biogenesis genes, suggesting that one mechanism by which DREF is required for growth is through the control of protein synthetic capacity. Together these findings suggest DREF is an essential transcription factor in the nutritional control of cell and tissue growth during Drosophila development. Given that DREF is conserved, this role may also be important in the control of growth in other animals.
营养物质的可获得性是动物生长的关键决定因素。保守的胰岛素/PI3 激酶和 TOR 激酶信号通路是两个最典型的细胞和组织生长的调节剂，可响应营养条件。在果蝇幼虫中的研究表明，这些通路驱动生长的一种机制是通过调节代谢基因的表达，特别是那些对蛋白质合成所必需的基因的表达。在这里，我们研究了转录因子 DREF 在介导这些转录和生长反应中的一些作用。我们发现，DREF 的缺失会导致生物体生长减少。这些影响部分是由于 DREF 功能在细胞自主生长中的需要。我们还发现 DREF 活性在幼虫脂肪体中具有非自主作用。先前的研究表明，TOR 在脂肪体中的激活将营养与来自大脑的胰岛素释放偶联；我们发现，脂肪体中 DREF 的抑制可以模拟营养剥夺和脂肪特异性 TOR 抑制的效果，导致全身胰岛素信号转导减少、幼虫生长延迟和最终体型变小。通过遗传上位性，我们发现 DREF 是 TOR 下游生长所必需的，但不是胰岛素/PI3K 信号。此外，我们表明 TOR 可以通过转录因子 dMyc 控制 DREF mRNA 水平。最后，我们表明 DREF 是许多核糖体生物发生基因正常表达所必需的，这表明 DREF 是生长所必需的一种机制，是通过控制蛋白质合成能力。这些发现表明，DREF 是果蝇发育过程中营养物质控制细胞和组织生长的必需转录因子。鉴于 DREF 是保守的，这个作用在其他动物的生长控制中也可能很重要。
