Redox Control of Signal Transduction,Gene Expression and Cellular Senescence

Reactive oxygen species (ROS) act as subcellular messengers in such complex cellular processes as mitogenic signal transduction, gene expression, regulation of cell proliferation, replicative senescence, and apoptosis. They serve to maintain cellular homeostasis and their production is under strict control. However, the mechanisms whereby ROS act are still obscure. Here we review recent advances in our understanding of signaling mechanisms and recent data about the involvement of ROS in: (i) the regulation of the mitogenic transduction elements, particularly protein kinases and phosphatases; (ii) the regulation of gene expression; and (iii) the induction of replicative senescence and the role, if any, in aging and age-related disorders.     

High NaCl Promotes Cellular Senescence

High extracellular NaCl was previously shown to increase the number of DNA breaks in mammalian cells in tissue culture, renal medullary cells in vivo, C. elegans, and marine invertebrates. It was also shown to increase reactive oxygen species in renal cells, resulting in oxidation of proteins and DNA. Cellular senescence is a common response to such damage. Therefore, in the present studies we looked for signs of senescence in cells exposed to high NaCl. We find that (1) The rate of proliferation of HeLa cells exposed to high NaCl decreases gradually to the point of arrest, and the cells display signs of senescence, including hypertrophy and increased auto fluorescence. (2) High NaCl accelerates the appearance of senescence in primary mouse embryonic fibroblasts, as measured by β-galactosidase activity (SA-β-gal). (3) High NaCl retards growth and markedly decreases the life span of C. elegans, accompanied by features of accelerated aging, such as decreased locomotion and increased number of SA-β-gal positive cells. (4) Mouse renal medullary cells, which are normally continuously exposed to high NaCl, express increased p16^INK4 (another indicator of senescence) much earlier than do cells in the renal cortex, which has the same level of NaCl as peripheral blood. We conclude that high NaCl accelerates cellular senescence and aging, most likely secondary to the DNA breaks and oxidative damage that it causes.     

细胞衰老与肿瘤治疗

人口老龄化是全世界都面临的重大挑战,随着老年人口的增加,肿瘤等衰老相关疾病发病率随之升高.流行病学调查结果显示,大约2/3的新增肿瘤患者为65岁以上的老年人,并且这一比例在不断攀升.细胞衰老是指在DNA损伤或癌基因失调等一系列条件下引起的稳定的细胞周期阻滞,并伴有形态、生化及表观遗传的改变.大量研究证明细胞衰老对抑制潜在癌细胞增殖具有重要作用.然而,目前研究认为除了抑制肿瘤发生,细胞衰老也可能促进肿瘤的演进,细胞衰老对肿瘤发挥了双刃剑作用.因此,深入了解细胞衰老与肿瘤之间的联系,充分利用细胞衰老对肿瘤抑制功能,规避其对肿瘤的促进作用可为肿瘤的治疗提供更多可能的选择.     

细胞衰老与衰老细胞

细胞衰老(cellular senescence)是一个应激导致细胞生长停滞的生理过程．一部分发生衰老的细胞会被机体自身清除,但另一些衰老的细胞会随着时间的推移在体内积累增多,并分泌一些免疫刺激因子,导致低水平炎症发生,引起周围组织衰老或癌变,这类具有特殊生物学特征和功能的细胞就是衰老细胞(senescent cell)．实验揭示,衰老细胞不仅是衰老过程的产物,也可能是组织器官进一步衰退的重要原因．近日,Baker等的一项研究成果(Nature,2011,479(7372)：232-236)表明,清除衰老细胞可延缓小鼠的衰老进程,该成果有望开辟出一条对抗衰老的新途径．     

NAD^+与细胞衰老

烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD^+)作为糖酵解、三羧酸循环和氧化磷酸化中关键酶的辅助因子,参与了细胞的物质代谢、能量合成、损伤DNA的修复等多种生理病理过程。近年来越来越多的研究发现,细胞内NAD^+水平在机体或细胞衰老过程中呈明显下降趋势,而补充NAD^+能延缓细胞/机体的衰老,使NAD^+及其前体物质在细胞衰老中的作用受到广泛关注。该文就NAD^+及其前体物质与细胞代谢、衰老的关系及相关分子机制研究的最新进展进行综述,以期深入认识NAD^+与细胞衰老的内在联系,为细胞衰老相关的基础及应用研究提供理论参考。     

Active Degradation Explains the Distribution of Nuclear Proteins during Cellular Senescence

The amount of cellular proteins is a crucial parameter that is known to vary between cells as a function of the replicative passages, and can be important during physiological aging. The process of protein degradation is known to be performed by a series of enzymatic reactions, ranging from an initial step of protein ubiquitination to their final fragmentation by the proteasome. In this paper we propose a stochastic dynamical model of nuclear proteins concentration resulting from a balance between a constant production of proteins and their degradation by a cooperative enzymatic reaction. The predictions of this model are compared with experimental data obtained by fluorescence measurements of the amount of nuclear proteins in murine tail fibroblast (MTF) undergoing cellular senescence. Our model provides a three-parameter stationary distribution that is in good agreement with the experimental data even during the transition to the senescent state, where the nuclear protein concentration changes abruptly. The estimation of three parameters (cooperativity, saturation threshold, and maximal velocity of the reaction), and their evolution during replicative passages shows that only the maximal velocity varies significantly. Based on our modeling we speculate the reduction of functionality of the protein degradation mechanism as a possible competitive inhibition of the proteasome.     

细胞衰老相关基因的探索

细胞衰老与个体衰老、机体自我保护及细胞癌变等多种重要生理、病理现象密切相关,其机制研究可望应用于癌症治疗.简述了近年有关哺乳类动物细胞衰老相关基因的寻找过程.     

细胞衰老与肿瘤发生及药物治疗

肿瘤细胞往往具有衰老障碍而表现出无限增殖的能力。细胞衰老障碍与肿瘤化疗和多药耐药关系密切,恢复肿瘤细胞衰老通路是肿瘤治疗和逆转多药耐药的一个很有前途的研究方向。     

Cellular Senescence,Epigenetic Switches and c-Myc

In response to hyperproliferative signaling elicited by transforming oncogenes some normal human cells can enter replicative senescence as a tumor defense mechanism. We recently found that human fibroblasts or endothelial cells with genetically-engineered reduction of proto-oncogene c-Myc expression switched with an increased frequency to a senescent state by a telomere-independent mechanism involving the polycomb group repressor Bmi-1 and the cyclin-dependent kinase inhibitor p16^INK4a. The same regulatory circuit was triggered upon exposure to mild oxidative stress. These findings point to the existence of a mechanism for monitoring hypoproliferative signaling, whose function may be to limit the proliferation and accretion of physiologically compromised cells. This mechanism may be another example of antagonistic pleiotropy leading to organismal aging.     

High-Resolution Ribosome Profiling Defines Discrete Ribosome Elongation States and Translational Regulation during Cellular Stress

1. Download high-res image (176KB)
2. Download full-size image

     

核因子Y在细胞衰老中的作用

核因子Ｙ(ｎｕｃｌｅａｒｆａｃｔｏｒＹ ,ＮＦ Ｙ)也称作ＣＢＦ(ＣＣＡＡＴｂｏｘｂｉｎｄｉｎｇｆａｃｔｏｒ)、ＣＰ1 ,是结合ＣＣＡＡＴ盒的转录因子。它能识别真核基因启动子区域的 5′ ＣＴＧＡＴＴＧＧＹＹＲＲ 3′或 5′ ＹＹＲＲＣＣＡＡＴＣＡＧ 3′共有序列。有功能的ＮＦ Ｙ是一个异源三聚体蛋白 ,它包含三个不同的亚单位Ａ、Ｂ、Ｃ。细胞衰老是由细胞分裂的次数决定的。控制细胞分裂的机制之一是调控Ｇ1 /Ｓ期的基因表达。当细胞衰老时 ,由于Ｇ1 /Ｓ基因调控的转变 ,细胞不能进入Ｓ期而只停留在Ｇ1期。ＮＦ Ｙ正是通过与Ｇ1 /Ｓ…     

衰老相关异染色质聚集——细胞衰老生物学新标志

染色质重塑是调控基因时序性表达的重要环节.衰老的人二倍体成纤维细胞核中有呈点状聚集的异染色质结构,这种特征性现象被称为衰老相关异染色质聚集(SAHF).K9M-H3和HP1是SAHF的标志性蛋白.在SAHF的形成过程中,p16INK4a/Rb途径和高迁移率蛋白A(high-mobility group A protein,HMGA protein)等许多因素起着非常重要的作用.最近研究表明,SAHF能够抑制E2F靶基因的表达,从而使细胞维持于稳定的衰老状态.SAHF的发现为细胞衰老的研究提供了一个新的生物学标志,并为细胞衰老状态的稳定维持提出了一种分子机制.     

Akt-Induced Cellular Senescence: Implication for Human Disease

Reduction-of-function mutations in components of the insulin/insulin-like growth factor-1/Akt pathway have been shown to extend the lifespan in organisms ranging from yeast to mice. It has also been reported that activation of Akt induces proliferation and survival of mammalian cells, thereby promoting tumorigenesis. We have recently shown that Akt activity increases with cellular senescence and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, leading to endothelial dysfunction. This novel role of Akt in regulating the cellular lifespan may contribute to various human diseases including atherosclerosis and diabetes mellitus.     

Polycomb蛋白复合体对细胞衰老的表观遗传学调控

细胞衰老在表观遗传学上的调控越来越受到人们的关注.Polycomb蛋白复合体(polycomb group proteins)通过对组蛋白的修饰,尤其是甲基化修饰发挥对靶基因的沉默作用,并因此广泛参与到发育、增殖、分化以及肿瘤发生等重要生命过程.目前,有一系列的研究报道了polycomb的各组份参与了细胞衰老的调控.本文对polycomb发挥基因沉默作用机制的最新研究进展进行了归纳总结,并以衰老过程中的重要分子p16为重点,详细介绍了polycomb调节p16表达,影响细胞衰老进程的机制.研究表明,多种polycomb成员同时结合在p16INK4a基因座,它们的结合表现出相互依赖的同时又有各自的作用.这为进一步深入理解细胞衰老提供了表观遗传学的证据.     

Molecular Mechanisms of Cellular Senescence in Neurodegenerative Diseases

Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are characterized by several pathological features, including selective neuronal loss, aggregation of specific proteins, and chronic inflammation. Aging is the most critical risk factor of these disorders. However, the mechanism by which aging contributes to the pathogenesis of neurodegenerative diseases is not clearly understood. Cellular senescence is a cell state or fate in response to stimuli. It is typically associated with a series of changes in cellular phenotypes such as abnormal cellular metabolism and proteostasis, reactive oxygen species (ROS) production, and increased secretion of certain molecules via senescence-associated secretory phenotype (SASP). In this review, we discuss how cellular senescence contributes to brain aging and neurodegenerative diseases, and the relationship between protein aggregation and cellular senescence. Finally, we discuss the potential of senescence modifiers and senolytics in the treatment of neurodegenerative diseases.