在11月的《自然·细胞生物学》杂志上，来自美国MCG癌症研究中心卡皮尔·巴拉教授的实验室任博士后研究员的杨永华（Yonghua Yang ,音译，第一作者）发表的最新研究显示，单向环境压力（one way environmental stress）是通过降低导致细胞死亡的一种酶的活性水平来引发癌症的。
杨博士解释说，他们发现压力诱导因子如氧化应激（oxidative stress）能够召集一种叫做SENP1的蛋白质，而这种蛋白能够从SIRT1酶切割走一种调节因子SUMO1,从而降低它的活性。他还解释说，这是使癌细胞变得很耐久的方法之一，他们单向生存得很好。有关癌症和压力关系的基础性发现增加SENP1活性的治疗开启了一扇门，从而使本该死的细胞走向死亡。
杨博士表示，他们想看看是否能阻碍增加癌细胞存活时间的过程，使癌细胞走向死亡。通常在癌症中表达的SIRT1的活性增加，能使癌细胞对化疗等抗癌药物产生更强的抗性。
杨永华称，他目前已经证实当利用SIRT1进行促癌和长寿研究时拥有不同的目标。
研究报告的另外一名作者兼塞西尔·F·惠特克以及乔治亚癌症研究联合协会著名学者巴拉称，这篇研究文章描述了应激如何导致SIRT1的和最终导致癌症的延迟蛋白修饰和蛋白修饰（desumoylation and sumoylation）过程。应激诱导因子可将SIRT-1酶与SENP1酶关联起来，因此细胞变得对应激诱导细胞凋亡更加有抗力。一旦SIRT1被延迟修饰，它的活性就会变低，而你却需要它的活性”。当SIRT1的活性降低时，一种肿瘤抑制基因p53就会变得更加的活跃。这种肿瘤抑制基因同样也能导致细胞凋亡。
在全身发现的SIRT1是一种通过一种叫做乙酰化作用的过程影响蛋白质功能的调节因子。MCG的研究人员还发现，SIRT1的蛋白修饰（与SUMO1结合）使它变得更加活跃，而这一过程需要蛋白修饰基序（能够促使SUMO1与SIRT1结合）才能发生。
Sirt1(Sirtuin type 1)是依赖于烟酰胺腺嘌呤二核苷酸(NAD+)的组蛋白脱乙酰酶, 为Sirtuins家族成员之一, 与细胞增殖、分化、衰老、凋亡和代谢密切相关.目前, 有关Sirt1与衰老和代谢的论文已在Science、Nature、Cell等杂志上连续刊出.其中, Sirt1通过抑制PPAR?促进白色脂肪细胞中脂肪动员, 并且通过下调肌细胞标志基因表达来抑制成肌细胞分化.提示Sirt1不仅是一个重要的与机体"长寿"有关的因子, 而且可能在动物脂肪沉积和肌肉发育中起着关键的调控作用。
原始出处:
Nature Cell Biology - 9, 1253 - 1262 (2007)
Published online: 14 October 2007; | doi:10.1038/ncb1645
SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress
Yonghua Yang1, 6, Wei Fu1, Jiandong Chen2, 3, Nancy Olashaw2, 3, Xiaohong Zhang1, 2, 3, Santo V. Nicosia1, 2, 4, Kapil Bhalla5 & Wenlong Bai1, 2, 3
1 Departments of Pathology and Cell Biology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, Florida 33612–4799, USA.
2 Department of Interdisciplinary Oncology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, Florida 33612–4799, USA.
3 Program of Molecular Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
4 Program of Experimental Therapeutics, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
5 Medical College of Georgia Cancer Center, 1120 15th Street, CN2101A, Augusta, GA 30912, USA.
6 Current address: Medical College of Georgia Cancer Center, 1120 15th Street, CN2101A, Augusta, GA 30912, USA.
Correspondence should be addressed to Wenlong Bai wbai@health.usf.edu
SIRT1 is the closest mammalian homologue of yeast SIR2, an important ageing regulator that prolongs lifespan in response to caloric restriction. Despite its importance, the mechanisms that regulate SIRT1 activity are unclear. Our study identifies a novel post-translational modification of SIRT1, namely sumoylation at Lys 734. In vitro sumoylation of SIRT1 increased its deacetylase activity. Conversely, mutation of SIRT1 at Lys 734 or desumoylation by SENP1, a nuclear desumoylase, reduced its deacetylase activity. Stress-inducing agents promoted the association of SIRT1 with SENP1 and cells depleted of SENP1 (but not of SENP1 and SIRT1) were more resistant to stress-induced apoptosis than control cells. We suggest that stress-inducing agents counteract the anti-apoptotic activity of SIRT1 by recruiting SENP1 to SIRT1, which results in the desumoylation and inactivation of SIRT1 and the consequent acetylation and activation of apoptotic proteins.
