凋亡抑制蛋白与细胞凋亡调控

Ｃａｓｐａｓｅｓ蛋白酶激活级联反应在凋亡调控中起核心作用,它主要涉及两条途径：死亡受体介导途径与线粒体依赖途径。不同的凋亡刺激信号经各自特定的途径起始不同的ｃａｓｐａｓｅｓ级联反应,进而激活下游的效应ｃａｓｐａｓｅｓ,诱发细胞凋亡。正常情况下细胞凋亡受到严密的调控以防因失调而导致机体病变。     

细胞凋亡与线粒体

细胞凋亡过程一般经过诱导－调控和执行－效应三个阶段。线粒体不仅对细胞凋亡的启动和调控具有重要意义,而且是细胞凋亡执行的关键元件。死亡信号诱使线粒体ＰＴ开启导致凋亡相关活性物质的释放。并继而对ｃａｓｐａｓｅ酶系激活是细胞凋亡实现的最基本的生物化学途径。     

BCL-2家族与线粒体对细胞凋亡的调控

线粒体是细胞凋亡调控的中心环节, 它通过释放膜间隙中的促凋亡蛋白(细胞色素C、Smac/DIABLO、AIF和en donucleaseG等)来起作用。线粒体膜间隙 (IMS)蛋白的释放是由BCL-2家族蛋白调控的。BCL-2家族蛋白能够诱导线粒体通透性转变孔道 (PT孔道 )的开放, 导致细胞凋亡。关于PT孔道开启的机制是近年来研究的一个热点。本文综述了近年来有关线粒体与BCL-2家族对细胞凋亡调控的研究进展。     

线粒体与细胞凋亡

线粒体是所有真核细胞内重要的细胞器 ,是ＡＴＰ生成的主要部位 ,对维持细胞能量代谢和正常功能活动起重要作用。新近研究发现 ,线粒体内包含一些与细胞凋亡有密切关系的物质 :如ｐｒｏ ｃａｓｐａｓｅ ,细胞色素Ｃ (ＣｙｔＣ) ,Ｓｍａｃ Ｄｉａｂｌｏ ,ＡＩＦ等。在一定因素的刺激下 ,线粒体膜的通透性增加 ,这些物质可由线粒体释出 ,诱导细胞凋亡。因此线粒体在细胞凋亡的发生中起重要作用 ,被形象地称为细胞凋亡的“燃烧室”。大多数细胞发生凋亡时均伴有 :(1)胞浆酸化 ;(2 )线粒体结构与功能障碍 ;(3)Ｃａｓｐａｓｅ活化。细胞发生凋亡…     

线粒体与细胞凋亡

细胞凋亡是一种由基因控制的细胞自杀性死亡过程 ,近年来成为生物学、医学领域的一个热点。通过对凋亡机制深入的研究 ,人们发现线粒体的改变已不仅是凋亡的特征 ,还是凋亡调控的中心环节。     

线粒体和细胞凋亡

细胞凋亡引起线粒体的一系列变化，主要表现为，线粒体膜电位降低、膜结构改变、生成的活性氧增多、转译及转录活动减少等。反之，线粒体主动参与凋亡过程，主要通过活性氧的直接作用、发生透性变化、释放可溶性因子等方式影响细胞凋亡     

细胞凋亡的线粒体调控与Bcl-2基因家族

线粒体结构和功能障碍是各种刺激因素诱导细胞凋亡的中心事件 ,由此导致线粒体内凋亡诱发因子释放 ,参与对细胞凋亡的调控 ;Bcl 2基因家族与此调控密切相关。     

线粒体与细胞凋亡

细胞凋亡过程中许多重要事件的发生都与线粒体密切相关,包括Caspases激活因子的释放,如细胞色素C(cytochromeC,CytC)、电子传递链的改变、线粒体膜电位(ΔΨm)的丧失、细胞内氧化还原状的改变、Bcl-2家族促进和抑制凋亡蛋白的参与等。不同信号的传导最终集中到线粒体上来启动或抑制这些事件及其效应的产生[1]。尽管凋亡的发生不依赖于氧化磷酸化,甚至不需要线粒体DNA(mtDNA)的参与,但是线粒体作为凋亡的中心环节已在许多凋亡系统中被证实。线粒体在细胞凋亡中作用的发现源于无核细胞凋亡的研究。1994年,Jacobson等把有核细胞去核制成…     

线粒体与细胞凋亡机制

细胞凋亡是生理性的细胞死亡过程,受到多种基因的精确调节。一类被统称为caspase的半胱氨酸蛋白酶是细胞凋亡程序的执行者,它们被激活后作用于细胞内的一些蛋白质,引起细胞凋亡。线粒体中含有许多凋亡相关因子,在凋亡信号转导中起着重要作用。细胞受到凋亡刺激 后,细胞色素c、AIF、caspase-9等凋亡相关因子从线粒体中释放出来。细胞色素c通过和Apaf-1、caspase-9相互作用,激活caspase-9,caspase-9激活下游的caspase蛋白酶。Bcl-2家族成员在细胞凋亡中起着重要的调控作用。     

线粒体膜通道与细胞凋亡

随着膜片钳技术的发展和新的研究手段的涌现 ,在细胞凋亡的作用机制中 ,线粒体途径正受到研究者越来越多的关注 ,而此途径中的基本因素离不开线粒体膜通道 ,综述就线粒体膜通道的类型 ,调控方式及其与细胞凋亡的关系     

Redox regulation of apoptosis: Impact of thiol oxidation status on mitochondrial function

The probability that a cell will undergo apoptosis is in part dictated by the cellular redox potential, which is mainly determined by the reduction and oxidation of thiol residues on glutathione and proteins. We and others have recently shown that mitochondria play a critical role in the apoptotic cascade. Here, we address the question as to whether thiol modification regulates apoptosis and in which cellular compartment apoptosis-regulatory thiols are localized. To resolve this problem, we employed the divalent thiol-reactive agent diamide, which causes thiol cross-linking and thus mimics disulfide bridge formation, and a panel of monovalent thiol-reactive compounds (which impede disulfide bridge formation due to thiol oxidation), one of which is specifically targeted to the mitochondrial matrix. Our data indicate that thymocyte apoptosis induced by diamide mimics natural apoptosis in the sense that mitochondrial transmembrane potential (ΔΨ_m) disruption precedes nuclear chromatin degradation: that monovalent thiol-reactive compounds inhibit apoptosis induced by diamide, glucocorticoids, irradiation, and topoisomerase inhibition; that the critical thiols determining cell fate after exposure to diamide, glucocorticoids, or DNA damage are likely to be located in the mitochondrial matrix; and that thiol oxidation and reduction are critical for apoptosis induction by some stimuli (glucocorticoids. DNA damage), but not by Fas/CD95 cross-linking. Taken together, these findings suggest that, at least in some pathways of apoptosis, mitochondrial thiols constitute a critical sensor of the cellular redox potential.     

T淋巴细胞凋亡及其调控机制的研究进展

T淋巴细胞凋亡是免疫系统维持稳定的一种重要机制,在多种疾病中起着重要作用.fas/FasL、Trail/trail受体等死亡受体信号传导可介导T淋巴细胞凋亡,线粒体在诱导细胞凋亡中也起着重要作用;而bcl-2家族、v-FLIP等抗细胞凋亡蛋白和转录因子Nur77等对T淋巴细胞凋亡起调控作用.     

中性粒细胞凋亡的线粒体死亡机制的研究进展

中性粒细胞是血细胞中寿命最短的终末分化细胞,在炎症反应中发挥着重要的作用,是人体免疫防御系统的第一道防线。与其它的血细胞和组织细胞在凋亡的发生机制上有所不同,中性粒细胞从分化成熟开始,就启动它的自发性凋亡程序。中性粒细胞自发性凋亡涉及到许多复杂的生化过程,线粒体是细胞的一种重要的细胞器,也是真核生物能量代谢的中心、凋亡中心,其在中性粒细胞凋亡信号传导和病理生理过程中起着关键性的调节作用。因此,对线粒体途径的调控机制进行研究是非常重要的。     

Ethanol promotes T cell apoptosis through the mitochondrial pathway

Clinical reports suggest that acute ethanol intoxication is often associated with lymphopenia. Previously, ethanol was reported to invoke thymocyte apoptosis. We studied the effect of ethanol on T cell apoptosis. In addition, we evaluated the molecular mechanism of ethanol-induced T cell apoptosis. Human T cells harvested from healthy subjects after an alcohol drinking binge showed enhanced T cell apoptosis (before, 0.4 +/- 0.2% versus after, 19.6 +/- 2.5% apoptotic lymphocytes/field; P < 0.001). In in vitro studies, ethanol in a concentration of 50 mm and higher enhanced the apoptosis of Jurkat cells. DNA isolated from ethanol-treated Jurkat cells displayed integer multiples of 180 base pairs. Ethanol decreased Jurkat cell expression of Bcl-2, whereas ethanol increased Jurkat cell expression of Bax. Jurkat cells treated with ethanol also showed translocation of cytochrome C into cytosol. Moreover, a caspase-9 inhibitor partially inhibited ethanol-induced Jurkat cell apoptosis. In in vivo studies, after binge drinking, T cell expression of Bcl-2 also decreased. In addition, binge drinking induced the cleavage of caspase-3, suggesting activation of caspase-3 in T cells. These results suggest that ethanol promotes T cell apoptosis through the activation of intrinsic or mitochondrial pathway.     

Role of hydrogen sulfide in the regulation of cell apoptosis

We studied the effect of a gas transmitter hydrogen sulfide (H₂S) on the realization of apoptosis in Jurkat cells and mononuclear leukocytes from healthy donors. Treatment with H₂S donor NaHS was accompanied by a dose-dependent intensification of cell death via apoptosis and necrosis. T-cell leukemia cells were more sensitive to H₂S than mononuclear leukocytes from healthy donors. H₂S-induced cell apoptosis was accompanied by activation of caspase-3 and caspase-9.     

Bak基因对Hela细胞的细胞周期和细胞凋亡的调控作用

目的 研究Ｂｃ１－２基因家族促凋亡蛋白Ｂａｋ在细胞凋亡细胞周期调控中的作用,评价它们作为肿瘤治疗的潜在靶基因的可能性。方法 采用一种可诱导性表达系统,（ＭＴ－Ⅱ调节系统）,在外加锌离子（ＺｎＳＯ４,１００μｍｏｌ／Ｌ）的条件下诱导Ｂａｋ基因表达。以Ｈｅｌａ细胞系作为靶细胞,获得表达Ｂａｋ基因的稳定转染子。结果 可诱导性Ｂａｋ基因过表达的Ｈｅｌａ细胞出现广泛死亡。ＴＵＮＥＬ染色证实细胞核碎片化,提示     

CREB-shRNA对氧糖剥夺/复氧皮层神经元线粒体形态和凋亡的影响

目的:探讨沉默CREB基因对氧糖剥夺/复氧神经元线粒体形态及细胞凋亡的影响。方法:3条靶向CREB基因的shRNA片段插入慢病毒载体pLenti Lox3.7(PLL),与包装质粒psPAX2和pMD2.G共转染293T细胞包装病毒颗粒后感染原代皮层神经元,Western blot检测CREB蛋白的沉默情况;分别用Mito Tracker red、TUNEL和Western blot实验检测氧糖剥夺/复氧诱导CREB基因沉默后神经元的线粒体形态、细胞凋亡和Bcl-2、Bax的表达情况。结果:pLL-CREB-shRNA1为最有效的shRNA,其抑制皮层神经元CREB基因表达率高达80%。CREB基因沉默促进氧糖剥夺/复氧诱导的皮层神经元线粒体向点状、片段化形态改变,同时降低Bcl-2表达、促进Bax的表达并加重细胞凋亡(P0.05)。结论:CREB-shRNA重组慢病毒载体可特异性抑制神经元CREB基因的表达,CREB基因沉默加重氧糖剥夺/复氧诱导的皮层神经元线粒体形态改变,促进细胞凋亡。     

Dlx2基因过表达与前成骨细胞系MC3T3-E1成骨分化过程中的细胞凋亡和周期调控*****◆

背景：Dlx2基因在颅神经嵴细胞迁徙进入第一鳃弓过程和颅颌面骨骼发育中起重要作用,但Dlx2基因对成骨细胞分化过程中细胞凋亡和细胞周期调控的影响尚未见报道。 目的：观察Dlx2基因过表达对前成骨细胞系MC3T3-E1成骨分化过程中细胞凋亡和细胞周期调控的影响。 方法：构建反转录病毒pMSCV-puro-Dlx2并转染矿化诱导液培养下的MC3T3-E1细胞,构建稳定过表达Dlx2基因的细胞系MC3T3-E1-Dlx2。RT-PCR和Western blot验证Dlx2基因过表达细胞系的建立。Annexin V/PI双染色后流式细胞分选检测细胞凋亡,PI/RNase双染色后流式细胞分选检测细胞周期变化。 结果与结论：实验成功构建稳定过表达Dlx2基因的细胞系MC3T3-E1-Dlx2。发现Dlx2基因过表达促进细胞凋亡(P < 0.05),同时阻滞细胞周期于G1/G0期(P < 0.05),减低细胞增殖性,促进细胞分化行使功能。 关键词：成骨细胞分化;Dlx2基因;稳定过表达;细胞凋亡;细胞周期 doi:10.3969/j.issn.1673-8225.2012.10.022     

Redox regulation of mitochondrial function

Redox-dependent processes influence most cellular functions, such as differentiation, proliferation, and apoptosis. Mitochondria are at the center of these processes, as mitochondria both generate reactive oxygen species (ROS) that drive redox-sensitive events and respond to ROS-mediated changes in the cellular redox state. In this review, we examine the regulation of cellular ROS, their modes of production and removal, and the redox-sensitive targets that are modified by their flux. In particular, we focus on the actions of redox-sensitive targets that alter mitochondrial function and the role of these redox modifications on metabolism, mitochondrial biogenesis, receptor-mediated signaling, and apoptotic pathways. We also consider the role of mitochondria in modulating these pathways, and discuss how redox-dependent events may contribute to pathobiology by altering mitochondrial function.