线粒体调控的细胞凋亡研究进展

细胞凋亡是指一种由基因控制的,细胞自主死亡的过程。其发生过程涉及细胞中多种信号转导通路的参与。其中线粒体在该过程中起到了关键的作用。病理条件下细胞内外环境的改变可通过影响线粒体的功能,从而调节细胞凋亡。笔者就目前线粒体调控的细胞凋亡机制的研究展开综述。主要介绍了线粒体结构功能改变与细胞凋亡、线粒体凋亡相关蛋白的释放及Bcl-2家族蛋白的介入等的最新研究进展。     

脑卒中与线粒体途径凋亡相关因子的研究进展

脑卒中导致的脑神经元凋亡过程中,存在着大量正性和负性的可调控相关因子,这些可调控因子可作为治疗脑卒中的潜在靶点。研究表明,脑卒中神经元细胞凋亡主要是由Caspase的级联反应所调控,细胞凋亡的主要途径之一是线粒体凋亡通路,Bcl-2家族蛋白主要调节Caspase的激活。线粒体释放的与凋亡相关的因子也对Caspase的激活有调节作用,而这些与凋亡相关的因子又受Bcl-2蛋白所调节。对脑卒中神经元凋亡过程中线粒体途径调控相关因子的研究是寻找和开发治疗脑卒中药物的重要理论基础。     

纳秒级电场脉冲诱导肿瘤细胞凋亡的线粒体通路研究

将纳秒级电场脉冲作用于人卵巢癌(SKOV3)细胞,通过流式细胞仪检测细胞活性氧(ROS)、线粒体跨膜电位(MTMP)的变化情况,用免疫荧光法检测线粒体膜间隙凋亡相关蛋白释放情况;用Western blot法检测线粒体膜间隙凋亡相关蛋白表达及活化情况,以研究纳秒级电场脉冲诱导肿瘤细胞凋亡的线粒体通路.实验发现:经纳秒级电场脉冲处理后,细胞活性氧即刻升高,且线粒体跨膜电位在6 h时达到最低值;线粒体膜间隙蛋白释放入胞浆(P<0.05);线粒体凋亡通路相关蛋白表达最也明显升高(P<0.05).结果表明,在纳秒级电场脉冲诱导的肿瘤细胞凋亡中,线粒体凋亡通路参与并发挥了重要作用.     

细胞凋亡的线粒体途径与缺血缺氧性肾损伤

“外源性通路”和“内源性通路”是细胞内凋亡信号转导的两条基本途径。线粒体作为内源性通路的中心环节在其中起主导作用。细胞凋亡时线粒体膜通透性增加,释放可溶性膜间隙蛋白（细胞色素,凋亡诱导因子,Smac／DIABLO等）,启动caspase级联反应和不依赖caspase途径的方式参与凋亡发生。Bcl-2蛋白家族以线粒体为靶位调控凋亡。线粒体凋亡途径也参与了肾缺血再灌注的损伤,其中炎症反应与细胞凋亡发生交互作用使得其损伤机制更为复杂。     

AIF及AIF依赖的细胞凋亡

AIF是一种线粒体蛋白 ,具有氧化还原酶和诱导细胞凋亡两种活性。AIF从线粒体到细胞核的转位足以介导体外细胞凋亡的发生 ,而且是以非caspases依赖的方式进行的。AIF的诱导凋亡活性是小鼠胚胎形态发生过程中类胚体成腔所必需的 ,也参与了神经细胞的细胞凋亡。真菌、线虫等的细胞凋亡也有AIF同源分子的参与。因此 ,AIF介导的细胞凋亡代表了独立于caspase信号通路之外的另一条更原始、更保守、更普遍的凋亡途径     

力学影响细胞凋亡及其信号转导机制研究进展

力学刺激会影响细胞凋亡的发生,进而影响组织器官结构和功能的变化,从而在机体的生理病理过程中起到重要作用,与很多疾病的发生发展密切相关。近年来力对细胞凋亡影响的信号转导机制逐渐开始受到细胞力学研究者的关注,现阶段部分实验研究结果显示力学刺激的形式、强度以及作用细胞种类的不同都会影响细胞凋亡,作用的过程和结果不尽相同。这一过程中的信号通路及其凋亡相关基因和蛋白的表达错综复杂,其中涉及的具体信号转导机制尚不明确。本文就细胞凋亡的特点、相关的信号通路、不同力学刺激对细胞凋亡的影响以及其信号转导通路的现阶段研究进展展开综述。     

线粒体在细胞凋亡中的作用及分子机制

本文综述了线粒体在细胞凋亡的启动和调控方面的最新进展。细胞受凋亡刺激，Bcl-2家族BH3蛋白(Bim，Bad，Bid等)和其他可能的途径将凋亡信号转入线粒体中，与Bcl-2家族凋亡诱导蛋白共同调节，诱导释放线粒体凋亡蛋白细胞色素c、caspase的二级线粒体激活蛋白Smac、凋亡诱导蛋白、内核酸酶G和Omi/HtrA2等，进而通过caspase依赖途径和非依赖途径诱导细胞凋亡。     

细胞凋亡通路研究进展

凋亡发生是一个主动过程 ,该过程的启动和进行受到基因的精确调控 ,目前发现细胞凋亡存在三条通路 :线粒体通路、死亡受体通路和内质网通路 ,各条通路间又有串话 (crosstalking) ,共同促进细胞凋亡。     

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。     

唯BH3域蛋白与细胞凋亡

唯BH3域蛋白是Bcl-2蛋白家族中的一类仅含有BH3同源区域的促凋亡分子。不同的凋亡刺激可以通过不同的途径活化不同的唯BH3域蛋白,且表现细胞类型特异性。唯BH3域蛋白通过与同一家族的其它抗凋亡或促凋亡蛋白相互作用,在启动线粒体通路中起重要作用。有些唯BH3域蛋白在内质网通路和死亡受体通路中也起到一定作用。对该类蛋白的研究将有助于深化对凋亡的认识,并为疾病治疗提供新的方法和思路。     

Twist的研究进展

Tw ist蛋白是属于碱性的螺旋-环-螺旋蛋白家族中的高度保守的转录因子,在胚胎的发生发展中发挥重要作用。Tw ist被认为是癌基因蛋白,影响肿瘤细胞的凋亡。Tw ist作为上皮-间质转变(ep ithelial-m esenchym altransition,EMT)过程中的关键调控因子,对肿瘤的侵袭和转移有重要影响。     

Eosinophil Survival and Apoptosis in Health and Disease

Eosinophilia is common feature of many disorders, including allergic diseases. There are many factors that influence the production, migration, survival and death of the eosinophil. Apoptosis is the most common form of physiological cell death and a necessary process to maintain but limit cell numbers in humans and other species. It has been directly demonstrated that eosinophil apoptosis is delayed in allergic inflammatory sites, and that this mechanism contributes to the expansion of eosinophil numbers within tissues. Among the proteins known to influence hematopoiesis and survival, expression of the cytokine interleukin-5 appears to be uniquely important and specific for eosinophils. In contrast, eosinophil death can result from withdrawal of survival factors, but also by activation of pro-apoptotic pathways via death factors. Recent observations suggest a role for cell surface death receptors and mitochondria in facilitating eosinophil apoptosis, although the mechanisms that trigger each of these death pathways remain incompletely delineated. Ultimately, the control of eosinophil apoptosis may someday become another therapeutic strategy for treating allergic diseases and other eosinophil-associated disorders.     

PI3K/AKT inhibition induces caspase-dependent apoptosis in HTLV-1-transformed cells

The phosphatidylinositol-3-kinase (PI3K) and AKT (protein kinase B) signaling pathways play an important role in regulating cell cycle progression and cell survival. In previous studies, we demonstrated that AKT is activated in HTLV-1-transformed cells and that Tax activation of AKT is linked to p53 inhibition and cell survival. In the present study, we extend these observations to identify regulatory pathways affected by AKT in HTLV-1-transformed cells. We demonstrate that inhibition of AKT reduces the level of phosphorylated Bad, an important member of the pro-apoptotic family of proteins. Consistent with the decrease of phosphorylated Bad, cytochrome c is released from the mitochondria and caspase-9 is activated. Pretreatment of the cells with caspase-9 specific inhibitor z-LEHD-FMK or pan caspase inhibitor Ac-DEVD-CHO prevented LY294002-induced apoptosis. Of interest, p53 siRNA prevents LY294002-induced apoptosis in HTLV-1-transformed cells, suggesting that p53 reactivation is linked to apoptosis. In conclusion, the AKT pathway is involved in targeting multiple proteins which regulate caspase- and p53-dependent apoptosis in HTLV-1-transformed cells. Since AKT inhibitors simultaneously inhibit NF-kappaB and activate p53, these drugs should be promising candidates for HTLV-1-associated cancer therapy.     

miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis

The execution of apoptosis is critical for proper development of the nervous system. However, it is equally important that neurons strictly inhibit apoptosis after development to ensure their survival throughout the lifetime of the organism. Here we show that a microRNA, miR-29b, is markedly induced with neuronal maturation and functions as a novel inhibitor of neuronal apoptosis. The prosurvival function of miR-29b is mediated by targeting genes in the proapoptotic BH3-only family. Our results identify a unique strategy evolved by maturing neurons that uses a single microRNA to inhibit the multiple, redundant BH3-only proteins that are key initiators of apoptosis.     

TNF-Induced Signaling in Apoptosis

Out of the almost 17 members of the TNF superfamily, TNF is probably the most potent inducer of apoptosis. TNF activates both cell-survival and cell-death mechanisms simultaneously. Activation of NF-kB-dependent genes regulates the survival and proliferative effects pf TNF, whereas activation of caspases regulates the apoptotic effects. TNF-induced apoptosis is mediated primarily through the activation of type I receptors, the death domain of which recruits more than a dozen different signaling proteins, which together are considered part of an apoptotic cascade. This cascade does not, however, account for the role of reactive oxygen intermediates, ceramide, phospholipases, and serine proteases which are also inplicated in TNF-induced apoptosis. This cascade also does not explain how type II TNF receptors which lack the death domain, induce apoptosis. Nevertheless, this review of apoptosis signaling will be limited to those proteins that makeup the cascade.     

HERPES SIMPLEX VIRUS INFECTION AND APOPTOSIS

Consequences of human herpes simplex virus (HSV) infection include the induction of apoptosis and the concomitant synthesis of proteins which act to block this process from killing the infected cell. Recent data has clarified our current understanding of the mechanisms of induction and prevention of apoptosis by HSV. These findings emphasize the fact that modulation of apoptosis by HSV during infection is a multicomponent phenomenon. We review recent evidence showing how this important human pathogen modulates the fundamental cell death process.     

Smac模拟物的抗肿瘤作用机制研究进展

肿瘤细胞对治疗因素产生耐受是治疗疗效受限的主因.凋亡抑制蛋白(IAPs)家族的高表达是肿瘤细胞产生治疗抗性的重要因素.Smac作为一种有效的促凋亡蛋白,可明显提高肿瘤细胞对放化疗的敏感性,促进肿瘤细胞凋亡;但是,外源Smac蛋白及其活性基团均不能进入细胞而发挥功能.因此,对于Smac模拟物的研发及其作用机制的探索成为研究人员关注的焦点.针对近年来Smac模拟物及其作用机制的研究进展进行综述.     

Lysosome Dysfunction Enhances Oxidative Stress‐Induced Apoptosis through Ubiquitinated Protein Accumulation in Hela Cells

The role of lysosomal system in oxidative stress‐induced apoptosis in cancer cells is not fully understood. Menadione is frequently used as oxidative stress model. It is indicated that menadione could induce autophagy in Hela cells. In the present study, we examined whether the lysosomal inhibitor, ammonium chloride (NH₄Cl) could prevent the autophagy flux by inhibiting the fusion of autophagosomes with lysosomes and enhance apoptosis induced by menadione via mitochondrial pathway. The results demonstrated generation and accumulation of reactive oxygen species and increased levels of ubiquitinated proteins and GRP78 in cells treated with both menadione and NH₄Cl. Our data indicates that lysosomal system through autophagy plays an important role in preventing menadione‐induced apoptosis in Hela cells by clearing misfolded proteins, which alleviates endoplasmic reticulum stress. Anat Rec, 2013. © 2012 Wiley Periodicals, Inc.     

Reduced apoptosis and increased inflammatory cytokines in granulomas caused by tuberculous compared to non-tuberculous mycobacteria: role of MPT64 antigen in apoptosis and immune response

Inhibition of apoptosis of infected macrophages by pathogenic mycobacteria is suggested to be an important virulence mechanism, but little is known about the mycobacterial proteins involved in the inhibition of apoptosis. In this study we investigated differences in apoptosis and immune response and their correlation with the expression of Mycobacterium tuberculosis complex-specific secretory protein MPT64 in lesions caused by tuberculous or non-tuberculous mycobacteria by analysing the in situ expression of apoptosis-related proteins (FasL, Fas, Bax, Bcl-2), apoptotic cells, inflammatory cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-10, transforming growth factor (TGF)-beta, interferon (IFN)-gamma] and MPT64 antigen. The discrimination of mycobacteria was made by nested polymerase chain reaction (PCR) amplification of IS6110, which is specific for M. tuberculosis complex organisms. Forty-seven cases of lymphadenitis with necrotic granulomas were evaluated. With nested PCR, 30/47 cases were positive for M. tuberculosis. MPT64 antigen was detected specifically in the PCR-positive cases. Granulomas caused by tuberculous mycobacteria had fewer apoptotic cells, higher numbers of cells expressing TNF-alpha and TGF-beta and less extensive necrosis than granulomas caused by non-tuberculous mycobacteria. There was a significant negative correlation between apoptotic cells and the number of cells expressing MPT64 antigens, suggesting a role for MPT64 protein in the inhibition of apoptosis. Granulomas with higher amounts of MPT64 also showed a greater number of cells expressing TGF-beta than those with lower amounts of MPT64. In conclusion, this study supports the hypothesis that inhibition of apoptosis is a virulence mechanism for tuberculous mycobacteria. Correlation of MPT64 antigen with expression of macrophage deactivating cytokines and reduced apoptosis suggests its role in pathogenesis and bacillary persistence.