McBurney Michael W, Clark-Knowles Katherine V, Caron Annabelle Z, Gray Douglas A
Program in Cancer Therapeutics, Ottawa Hospital Research Institute ; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
Genes Cancer. 2013 Mar;4(3-4):125-34. doi: 10.1177/1947601912474893.
SIRT1 is a NAD(+)-dependent protein deacetylase that has a very large number of established protein substrates and an equally impressive list of biological functions thought to be regulated by its activity. Perhaps as notable is the remarkable number of points of conflict concerning the role of SIRT1 in biological processes. For example, evidence exists suggesting that SIRT1 is a tumor suppressor, is an oncogene, or has no effect on oncogenesis. Similarly, SIRT1 is variably reported to induce, inhibit, or have no effect on autophagy. We believe that the resolution of many conflicting results is possible by considering recent reports indicating that SIRT1 is an important hub interacting with a complex network of proteins that collectively regulate a wide variety of biological processes including cancer and autophagy. A number of the interacting proteins are themselves hubs that, like SIRT1, utilize intrinsically disordered regions for their promiscuous interactions. Many studies investigating SIRT1 function have been carried out on cell lines carrying undetermined numbers of alterations to the proteins comprising the SIRT1 network or on inbred mouse strains carrying fixed mutations affecting some of these proteins. Thus, the effects of modulating SIRT1 amount and/or activity are importantly determined by the genetic background of the cell (or the inbred strain of mice), and the effects attributed to SIRT1 are synthetic with the background of mutations and epigenetic differences between cells and organisms. Work on mice carrying alterations to the Sirt1 gene suggests that the network in which SIRT1 functions plays an important role in mediating physiological adaptation to various sources of chronic stress such as calorie restriction and calorie overload. Whether the catalytic activity of SIRT1 and the nuclear concentration of the co-factor, NAD(+), are responsible for modulating this activity remains to be determined. However, the effect of modulating SIRT1 activity must be interpreted in the context of the cell or tissue under investigation. Indeed, for SIRT1, we argue that context is everything.
SIRT1是一种依赖烟酰胺腺嘌呤二核苷酸（NAD⁺）的蛋白质脱乙酰酶，它有大量已确定的蛋白质底物，其活性被认为可调节的生物学功能列表同样令人印象深刻。或许同样值得注意的是，关于SIRT1在生物学过程中的作用存在大量相互矛盾的观点。例如，有证据表明SIRT1是一种肿瘤抑制因子、是一种癌基因，或者对肿瘤发生没有影响。同样，关于SIRT1对自噬的作用，有不同的报道称其可诱导、抑制或无影响。我们认为，通过考虑最近的报道，许多相互矛盾的结果有可能得到解决，这些报道表明SIRT1是一个重要的枢纽，与一个复杂的蛋白质网络相互作用，共同调节包括癌症和自噬在内的多种生物学过程。许多相互作用的蛋白质本身就是枢纽，就像SIRT1一样，利用内在无序区域进行广泛的相互作用。许多研究SIRT1功能的实验是在对构成SIRT1网络的蛋白质进行了数量不确定的改变的细胞系上进行的，或者是在携带影响其中一些蛋白质的固定突变的近交系小鼠上进行的。因此，调节SIRT1数量和/或活性的效果在很大程度上取决于细胞（或小鼠近交系）的遗传背景，归因于SIRT1的效应是与细胞和生物体之间的突变背景及表观遗传差异综合产生的。对携带Sirt1基因改变的小鼠的研究表明，SIRT1发挥作用的网络在介导对各种慢性应激源（如热量限制和热量过载）的生理适应中起重要作用。SIRT1的催化活性和辅助因子NAD⁺的核浓度是否负责调节这种活性仍有待确定。然而，调节SIRT1活性的效果必须在正在研究的细胞或组织的背景下进行解释。事实上，对于SIRT1，我们认为背景就是一切。
