FasL,Fas介导的细胞凋亡与肝脏疾病

细胞凋亡、或程序性细胞死亡(PCD)是机体在生长、发育及维持内部平衡过程中发生的正常细胞的生理性死亡现象。近来研究证实FasL(Fas配体)与Fas是介导细胞凋亡的一对膜蛋白。FasL、Fas以膜分子或可溶性分子的形式存在,与参与其信号途径调控的许多细胞内外因子共同组成Fas系统,在维持组织正常发育、控制免疫反应、调节机体生理平     

细胞凋亡与结核病

细胞凋亡(apoptosis)是指细胞在一定条件下,受自身基因调控,自行结束生命活动的过程,也是细胞衰老死亡的一种主动过程,因其发生受基因的调控并按一定的程序进行,故又称为细胞程序性死亡(programmedcelldeath ,PCD)。近来研究发现,细胞凋亡在结核病发生、发展过程中起着重要作用,细胞凋亡参与了机体抗结核保护性免疫过程[1,2 ] 。我们就细胞凋亡与结核病有关的研究及其进展作一综述。一、结核病时细胞凋亡的相关调控基因、途径与诱导因素(一)Fas/FasL系统及其诱导的凋亡过程Fas系统包括Fas、Fas配体(FasL)及它们的可溶形式。细胞毒T细胞…     

非编码RNA在卵巢癌中的研究现状

细胞内存在成千上万种非编码RNA(non-coding RNA,ncRNA),人们对ncRNA的认识从最初的转录垃圾已转变为功能调控分子。ncRNA参与介导细胞过程,包括染色质重构、转录、转录后修饰,在许多疾病中扮演着关键调控因子,特别是在恶性肿瘤中可作为致癌因子和抑癌因子驱动特定的细胞生物活动。迄今为止,卵巢癌的发病病因尚不明确,探索ncRNA在卵巢癌细胞中的作用及机制,有助于为卵巢癌的研究提供新的思路。现就卵巢癌相关的ncRNA的研究现状,尤其是微小RNA(miRNA)、长链非编码RNA(lncRNA)及环状RNA(circRNA)作一综述。     

细胞凋亡与肝脏疾病

细胞凋亡(apoptosis,APO)是指在一定的生理和病理情况下,机体为维护内环境的稳定,通过基因调控而使细胞自动消亡的过程.英国Kerr教授1972年首先提出凋亡的概念,他主要根据形态学上的不同将细胞凋亡与坏死相区分,并指出前者是一种主动的、程序性的、细胞固有的过程许多文献又称凋亡为程序性细胞死亡(programmed cell death,PCD),而最新观念认为APO是形态学上的概念,PCD是发生机制上的概念,不是所有PCD都表现为APO,因而可以认为APO是PCD的一种形态学表现[1].1980年以来,细胞凋亡现象受到了广泛重视,有关的研究工作取得了重要进展,并成为医学生物学各学科所共同关注的极为活跃的研究领域[2-19].     

非编码RNA对肿瘤的调控机制

非编码RNA(ncRNA)是不参与蛋白质编码的RNA的总称,包括微小RNA(miRNA)、长链非编码RNA(lncRNA)、转运RNA(tRNA)、核糖体RNA (rRNA)等.研究发现,ncRNA在调节组织细胞的发生、分化、增殖、凋亡等方面具有重要的作用.尤其在肿瘤细胞中,ncRNA的表达水平与正常细胞有明显差异,在功能上表现为致癌基因或抑癌基因,提示其在肿瘤的发生发展中可能起重要作用.此文对当前研究较为深入的几种ncRNA调控肿瘤的机制作一综述.     

细胞凋亡与大肠肿瘤

0 引言 细胞凋亡是维持个体正常生理过程的自主性细胞死亡形式,有其特征性形态学改变和生物化学变化。在许多情况下,细胞凋亡亦称为细胞程序性死亡(programmed cell death,PCD)。但也有人认为,从严格意义来说,二者是有区别的,PCD是发生于生长发育过程中特定时间范围内的细胞死亡,而凋亡则是瞬时性的细胞死亡。细胞凋亡不仅与肿瘤发生有关,而且也将为肿瘤治疗提供新的途径。     

microRNA对干细胞调控作用的研究进展

核糖核酸(RNA),是广泛存在于生物体内的重要遗传信息载体。其中,能翻译成蛋白质的RNA分子称为编码RNA,也称信使RNA(mRNA),不能翻译成蛋白质的RNA分子称非编码RNA(ncRNA)。微小RNA(miRNA)是ncRNA的一种,于1993年首次在线虫体内发现〔1〕。随着研究的不断深入,人们发现microRNA在基因转录后的调控方面发挥重要作用,它广泛参与细胞间信号传导及参与细胞代谢、生长、增殖、分化、凋亡等多方面的生物进程。当microRNA调控功能发生障碍,可能导致一些基因的异常表达〔2〕。     

细胞凋亡与肝细胞肝癌

细胞凋亡是细胞自然衰老、死亡的一种形式,其退化或受抑参与包括肝细胞肝癌在内的各种恶性肿瘤的发生与发展过程,许多因素调控和影响着肝癌的细胞凋亡。     

癌基因与抑癌基因和细胞程序化死亡及肿瘤治疗的策略

近年来的研究表明,在肿瘤形成和演化的多步骤过程中,癌基因、抑癌基因与细胞凋亡(APO)或程序化细胞死亡(PCD)过程有相当重要的联系。本综述将阐明主要癌基因、抑癌基因参与肿瘤PCD的研究进展及当今肿瘤治疗的新思路。 1 程序化死亡和肿瘤生物学行为 早在1980年,Wyllie等就发现肿瘤细胞发生凋亡     

细胞调亡与肝细胞肝癌

细胞凋亡是细胞自然衰老、死亡的一种形式，其退化或受抑参与包括肝细胞肝癌在的各种恶性肿瘤的发生与发展过程，许多因素调控和影响着肝癌的细胞凋亡。     

Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma

Although expression of non-protein-coding RNA (ncRNA) can be altered in human cancers, their functional relevance is unknown. Ultraconserved regions are noncoding genomic segments that are 100% conserved across humans, mice, and rats. Conservation of gene sequences across species may indicate an essential functional role, and therefore we evaluated the expression of ultraconserved RNAs (ucRNA) in hepatocellular cancer (HCC). The global expression of ucRNAs was analyzed with a custom microarray. Expression was verified in cell lines by real-time PCR or in tissues by in situ hybridization using tissue microarrays. Cellular ucRNA expression was modulated with siRNAs, and the effects on global gene expression and growth of human and murine HCC cells were evaluated. Fifty-six ucRNAs were aberrantly expressed in HepG2 cells compared with nonmalignant hepatocytes. Among these ucRNAs, the greatest change was noted for ultraconserved element 338 (uc.338), which was dramatically increased in human HCC compared with noncancerous adjacent tissues. Although uc.338 is partially located within the poly(rC) binding protein 2 (PCBP2) gene, the transcribed ncRNA encoding uc.338 is expressed independently of PCBP2 and was cloned as a 590-bp RNA gene, termed TUC338. Functional gene annotation analysis indicated predominant effects on genes involved in cell growth. These effects were experimentally demonstrated in both human and murine cells. siRNA to TUC338 decreased both anchorage-dependent and anchorage-independent growth of HCC cells. These studies identify a critical role for TUC338 in regulation of transformed cell growth and of transcribed ultraconserved ncRNA as a unique class of genes involved in the pathobiology of HCC.     

Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is mediated through a novel reactive oxygen species-dependent pathway

Monoclonal antibodies (mAbs) have revolutionized the treatment of B-cell malignancies. Although Fc-dependent mechanisms of mAb-mediated tumor clearance have been extensively studied, the ability of mAbs to directly evoke programmed cell death (PCD) in the target cell and the underlying mechanisms involved remain under-investigated. We recently demonstrated that certain mAbs (type II anti-CD20 and anti-HLA DR mAbs) potently evoked PCD through an actin-dependent, lysosome-mediated process. Here, we reveal that the induction of PCD by these mAbs, including the type II anti-CD20 mAb GA101 (obinutuzumab), directly correlates with their ability to produce reactive oxygen species (ROS) in human B-lymphoma cell lines and primary B-cell chronic lymphocytic leukemia cells. ROS scavengers abrogated mAb-induced PCD indicating that ROS are required for the execution of cell death. ROS were generated downstream of mAb-induced actin cytoskeletal reorganization and lysosome membrane permeabilization. ROS production was independent of mitochondria and unaffected by BCL-2 overexpression. Instead, ROS generation was mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. These findings provide further insights into a previously unrecognized role for NADPH oxidase-derived ROS in mediating nonapoptotic PCD evoked by mAbs in B-cell malignancies. This newly characterized cell death pathway may potentially be exploited to eliminate malignant cells, which are refractory to conventional chemotherapy and immunotherapy.     

慢性髓细胞性白血病病程进展中调节蛋白c-Myc、Bcl-2及Fas的表达变化

目的了解细胞程序死亡（ＰＣＤ）与慢性髓细胞性白血病（ＣＭＬ）急变的关系。方法采用流式细胞术，测定２１例ＣＭＬ及１２例正常骨髓标本单个核细胞的髓系免疫表型及三种与ＰＣＤ有关的调节蛋白——ｃ－Ｍｙｃ、Ｂｃｌ－２、Ｆａｓ的表达。结果与未治慢性期比较，加速／急变期膜抗原最显著的变化是ＨＬＡ－ＤＲ＋％的提高，ＣＤ＋１５％／ＨＬＡ－ＤＲ＋％比值倒置。正常骨髓及ＣＭＬ各期ＨＬＡ－ＤＲ＋及ＨＬＡ－ＤＲ－细胞几乎均表达ｃ－Ｍｙｃ，差别只在于表达量的多少，未治慢性期与正常骨髓组相似，加速／急变期组不仅显著高于未治慢性期组，其ＨＬＡ－ＤＲ＋细胞群的ｃ－Ｍｙｃ表达量亦显著高于正常骨髓组。Ｂｃｌ－２＋％在未治慢性期低于正常骨髓，加速／急变期组显著提高。Ｆａｓ在ＣＭＬ各期及正常骨髓均为低表达。结论处于未治慢性期的中、晚幼粒细胞的大量聚集似乎与Ｂｃｌ－２、Ｆａｓ的ＰＣＤ调节作用无关；而在加速／急变期组尤其是造血祖细胞不仅有增殖过旺，亦存在ＰＣＤ受阻     

Identification of immunosuppressant-induced apoptosis in a murine B-cell line and its prevention by bcl-x but not bcl-2.

Cyclosporin A, FK-506, and rapamycin are immunosuppressants often used as pharmacological probes to study lymphocyte activation and physiological cell death (PCD). Because cyclosporin A and FK-506 are known to prevent PCD in T-cell hybridomas and thymocytes, we used these reagents, as well as rapamycin, to determine whether they alter the pathway leading to apoptosis in murine WEHI-231 cells following surface IgM cross-linking. We observed that the immunosuppressants themselves induced PCD in WEHI-231 cells, but only in sublines susceptible to anti-IgM-mediated apoptosis. PCD was preceded by growth arrest and characterized by the DNA fragmentation pattern typical of apoptosis. In B-cell lines resistant to anti-immunoglobulin- and immunosuppressant-induced PCD, cyclosporin A, FK-506, and rapamycin caused growth arrest. PCD was also induced by inhibitors of protein synthesis in WEHI-231 cells but not in the mature B-cell line BAL-17. Immunosuppressant-induced and protein synthesis inhibitor-induced PCD, but not growth arrest, could be prevented by the overexpression of bcl-xL, while transfection with bcl-2 did not affect PCD or cell cycle arrest. These results suggest that bcl-2 and bcl-xL may control partially independent systems to inhibit PCD in lymphoid cells and that PCD in B and T cells may be differentially regulated.     

Prevention of Cellular Suicide by Cytomegaloviruses

As intracellular parasites, viruses rely on many host cell functions to ensure their replication. The early induction of programmed cell death (PCD) in infected cells constitutes an effective antiviral host mechanism to restrict viral spread within an organism. As a countermeasure, viruses have evolved numerous strategies to interfere with the induction or execution of PCD. Slowly replicating viruses such as the cytomegaloviruses (CMVs) are particularly dependent on sustained cell viability. To preserve viability, the CMVs encode several viral cell death inhibitors that target different key regulators of the extrinsic and intrinsic apoptosis pathways. The best-characterized CMV-encoded inhibitors are the viral inhibitor of caspase-8-induced apoptosis (vICA), viral mitochondrial inhibitor of apoptosis (vMIA), and viral inhibitor of Bak oligomerization (vIBO). Moreover, a viral inhibitor of RIP-mediated signaling (vIRS) that blocks programmed necrosis has been identified in the genome of murine CMV (MCMV), indicating that this cell death mode is a particularly important part of the antiviral host response. This review provides an overview of the known cell death suppressors encoded by CMVs and their mechanisms of action.     

Temporal and spatial activation of caspase-like enzymes induced by self-incompatibility in Papaver pollen

Caspase-like proteases are universal mediators of programmed cell death (PCD). Because plants have no caspase homologs, establishing the nature of their caspase-like activities is of considerable importance to our understanding of PCD in plants. Caspase-3, displaying DEVD specificity, is a key executioner caspase in animal cells. Self-incompatibility (SI) is an important mechanism to prevent self-fertilization and inbreeding in higher plants by inhibiting incompatible pollen. In Papaver rhoeas, SI activates a caspase-3-like/DEVDase activity in incompatible pollen that plays a pivotal role in regulating PCD. Here we characterize the SI-induced caspase-like activities in detail; our work provides insights into the temporal and spatial activation of plant caspase-like enzymes. We show that SI also activates a VEIDase and a LEVDase and that the VEIDase plays a role in SI-induced PCD. The DEVDase and VEIDase are activated remarkably rapidly: detectable within 1-2 h after SI induction; the LEVDase activity peaks later. Importantly, we show live-cell imaging of a DEVDase activity in a higher plant cell; the SI-activated DEVDase has a cytosolic and nuclear localization. We also demonstrate that SI induces a rapid and substantial cytosolic acidification that matches the in vitro pH optima for the SI-induced caspase activities. Because both cytosolic acidification and nuclear caspase localization are observed during apoptosis in animal cells, our data provide striking parallels between SI-induced PCD and apoptosis in animal cells.     

Failure of programmed cell death and differentiation as causes of tumors: some simple mathematical models.

Most models of tumorigenesis assume that the tumor grows by increased cell division. In these models, it is generally supposed that daughter cells behave as do their parents, and cell numbers have clear potential for exponential growth. We have constructed simple mathematical models of tumorigenesis through failure of programmed cell death (PCD) or differentiation. These models do not assume that descendant cells behave as their parents do. The models predict that exponential growth in cell numbers does sometimes occur, usually when stem cells fail to die or differentiate. At other times, exponential growth does not occur: instead, the number of cells in the population reaches a new, higher equilibrium. This behavior is predicted when fully differentiated cells fail to undergo PCD. When cells of intermediate differentiation fail to die or to differentiate further, the values of growth parameters determine whether growth is exponential or leads to a new equilibrium. The predictions of the model are sensitive to small differences in growth parameters. Failure of PCD and differentiation, leading to a new equilibrium number of cells, may explain many aspects of tumor behavior--for example, early premalignant lesions such as cervical intraepithelial neoplasia, the fact that some tumors very rarely become malignant, the observation of plateaux in the growth of some solid tumors, and, finally, long lag phases of growth until mutations arise that eventually result in exponential growth.     

Seminal plasma induces programmed cell death in cultured peripheral blood mononuclear cells

Immunosuppressive properties of seminal plasma inhibit the recovery of infectious HIV from semen, and led to the view early in the pandemic that semen HIV was transmitted principally by infected semen cells. More recent studies have revealed significant titers of HIV RNA in seminal plasma, however, even from men receiving successful antiviral therapy. Thus, studies of infectious HIV in seminal plasma are important to understanding sexual transmission and response to therapy. The present studies were undertaken to determine whether seminal plasma immunosuppression is mediated by the induction of programmed cell death (PCD). Peripheral blood mononuclear cells (PBMCs) were cultured without or with phytohemagglutinin and seminal plasma from normal donors, or men postvasectomy, or seminal vesicle protein collected at surgery. PBMC survival was measured at 3, 6, and 18 hr of culture; cells were examined for evidence of PCD by uptake of the fluorescent dye YO-PRO, and for fragmented nuclear DNA by the TUNEL assay. Approximately 90% of PBMCs cultured with seminal plasma from intact or vasectomized men were lost during 18 hr of culture; seminal vesicle protein did not induce cell loss. PCD assays were positive for PBMCs exposed to the seminal plasma, and negative for PBMCs cultured with seminal vesicle protein. Serum was not required for PCD induction. A 3-hr pulse with seminal plasma was sufficient to initiate PCD. These findings indicate that PCD induction accounts for the cytotoxic properties of semen, that the PCD is not the result of semen amine oxidases, and either that substances produced by seminal vesicles only at ejaculation, or by the prostate, are responsible for PCD induction.