Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
PLoS One. 2012;7(2):e31577. doi: 10.1371/journal.pone.0031577. Epub 2012 Feb 21.
Aging in organisms as diverse as yeast, nematodes, and mammals is delayed by caloric restriction, an effect mediated by the nutrient sensing TOR, RAS/cAMP, and AKT/Sch9 pathways. The transcription factor Gis1 functions downstream of these pathways in extending the lifespan of nutrient restricted yeast cells, but the mechanisms involved are still poorly understood. We have used gene expression microarrays to study the targets of Gis1 and the related protein Rph1 in different growth phases. Our results show that Gis1 and Rph1 act both as repressors and activators, on overlapping sets of genes as well as on distinct targets. Interestingly, both the activities and the target specificities of Gis1 and Rph1 depend on the growth phase. Thus, both proteins are associated with repression during exponential growth, targeting genes with STRE or PDS motifs in their promoters. After the diauxic shift, both become involved in activation, with Gis1 acting primarily on genes with PDS motifs, and Rph1 on genes with STRE motifs. Significantly, Gis1 and Rph1 control a number of genes involved in acetate and glycerol formation, metabolites that have been implicated in aging. Furthermore, several genes involved in acetyl-CoA metabolism are downregulated by Gis1.
在酵母、线虫和哺乳动物等多种生物中，通过热量限制来延缓衰老，这一效应是由营养感应 TOR、RAS/cAMP 和 AKT/Sch9 途径介导的。转录因子 Gis1 作为这些途径的下游因子，在延长营养限制的酵母细胞寿命方面发挥作用，但涉及的机制仍知之甚少。我们使用基因表达微阵列研究了 Gis1 和相关蛋白 Rph1 在不同生长阶段的靶标。我们的结果表明，Gis1 和 Rph1 既作为抑制剂，也作为激活剂，作用于重叠的基因集和不同的靶标。有趣的是，Gis1 和 Rph1 的活性和靶标特异性都依赖于生长阶段。因此，这两种蛋白都与指数生长期的抑制有关，在启动子中靶向具有 STRE 或 PDS 基序的基因。在双相转换后，两者都参与激活，Gis1 主要作用于具有 PDS 基序的基因，而 Rph1 作用于具有 STRE 基序的基因。重要的是，Gis1 和 Rph1 控制了许多参与乙酸盐和甘油形成的基因，这些代谢物与衰老有关。此外，Gis1 下调了几个参与乙酰辅酶 A 代谢的基因。
