自噬在细胞存活和死亡中的作用

自噬是亚细胞膜结构发生动态变化并经溶酶体介导对细胞内蛋白质和细胞器降解的过程.通过平衡细胞合成和分解代谢,自噬稳定细胞内环境,维持细胞的存活.然而,过度自噬可导致细胞发生Ⅱ型程序性细胞死亡.自噬与凋亡在细胞死亡过程中的关系十分密切.本文对自噬的过程及其在细胞存活和死亡中的作用作一综述.     

Autophagic cell death exists

The term autophagic cell death (ACD) initially referred to cell death with greatly enhanced autophagy, but is increasingly used to imply a death-mediating role of autophagy, as shown by a protective effect of autophagy inhibition. In addition, many authors require that autophagic cell death must not involve apoptosis or necrosis. Adopting these new and restrictive criteria, and emphasizing their own failure to protect human osteosarcoma cells by autophagy inhibition, the authors of a recent Editor’s Corner article in this journal argued for the extreme rarity or nonexistence of autophagic cell death. We here maintain that, even with the more stringent recent criteria, autophagic cell death exists in several situations, some of which were ignored by the Editor’s Corner authors. We reject their additional criterion that the autophagy in ACD must be the agent of ultimate cell dismantlement. And we argue that rapidly dividing mammalian cells such as cancer cells are not the most likely situation for finding pure ACD.     

Autophagic cell death exists

The term autophagic cell death (ACD) initially referred to cell death with greatly enhanced autophagy, but is increasingly used to imply a death-mediating role of autophagy, as shown by a protective effect of autophagy inhibition. In addition, many authors require that autophagic cell death must not involve apoptosis or necrosis. Adopting these new and restrictive criteria, and emphasizing their own failure to protect human osteosarcoma cells by autophagy inhibition, the authors of a recent Editor's Corner article in this journal argued for the extreme rarity or nonexistence of autophagic cell death. We here maintain that, even with the more stringent recent criteria, autophagic cell death exists in several situations, some of which were ignored by the Editor's Corner authors. We reject their additional criterion that the autophagy in ACD must be the agent of ultimate cell dismantlement. And we argue that rapidly dividing mammalian cells such as cancer cells are not the most likely situation for finding pure ACD.     

Autophagy and cell death

Autophagy exerts dual functions in cancer, acting as both a tumor suppressor, for example, by preventing the accumulation of damaged proteins and organelles, and as a tumor promoter that supports tumor growth. Many anticancer therapies engage autophagy as part of a cellular response. However, the question of whether or not autophagic activity in cells undergoing cell death is the cause of death or whether it is actually an attempt to support survival in response to cellular stress conditions has been discussed with great controversy.     

The tumour necrosis factor receptor family: life or death choices

The past twelve months have seen a renewal of interest in the therapeutic potential of members of the tumour necrosis factor receptor family and their cytokine ligands. This biomedical interest has spawned a number of structural studies, which have significantly deepened our understanding of the molecular basis for the function of these cell-surface signalling systems. The fresh data have revealed unexpected mechanisms conferring ligand-receptor specificity and have highlighted the structural requirements for the initiation of intracellular signalling.     

程序性细胞死亡与肿瘤

程序性细胞死亡（programmed cell death,PCD）是指由基因控制的细胞自主的有序性死亡方式,涉及一系列基因的激活、表达以及调控等。目前,经典细胞凋亡被称为Ⅰ型PCD,而自噬性细胞死亡称为Ⅱ型PCD,坏死样程序性细胞死亡则被称为Ⅲ型PCD,它们在肿瘤的发生、发展及治疗过程中起非常重要的作用。该文结合国内外最新研究进展主要针对不同细胞死亡模式及其相互作用、关键作用蛋白,细胞自噬与肿瘤发生,细胞自噬、凋亡与肿瘤治疗作一简要综述,并展望发展前景,提出在肿瘤治疗中如何利用不同死亡模式的协同作用最大限度地发挥其临床应用价值。     

植物细胞程序化死亡的形态学和生理生化特征

植物细胞程序化死亡(PCD)是一种由基因控制的、主动的细胞死亡过程,它在植物正常生长发育过程中起着重要作用。发生程序化死亡的植物细胞在形态、生理生化方面表现出一些共性特点和个性特点,该文对这些特点进行了综述。     

Interdigital cell death function and regulation: new insights on an old programmed cell death model

Interdigital cell death (ICD) is the oldest and best-studied model of programmed cell death (PCD) in vertebrates. The classical view of ICD function is the separation of digits by promotion of tissue regression. However, in addition, ICD can contribute to digit individualization by restricting interdigital tissue growth. Depending on the species, the relative contribution of either regression or growth-restricting functions of ICD to limb morphogenesis may differ. Under normal conditions, most cells appear to die by apoptosis during ICD. Accordingly, components of the apoptotic machinery are found in the interdigits, though their role in the initiation and execution of cell death is yet to be defined. Fgf8 has been identified as a survival factor for the distal mesenchymal cells of the limb such that ICD can initiate following specific downregulation of Fgf8 expression in the ectoderm overlying the interdigital tissue. On the other hand, Bmps may promote cell death directly by acting on the interdigital tissue, or indirectly by downregulating Fgf8 expression in the ectoderm. In addition, retinoic acid can activate ICD directly or through a Bmp-mediated mechanism. Interactions at different levels between these factors establish the spatiotemporal patterning of ICD activation. Defining the regulatory network behind ICD activation will greatly advance our understanding of the mechanisms controlling PCD in general.     

动物细胞培养过程中的细胞自然凋亡

细胞培养过程中的细胞自然凋亡是细胞受环境压力的影响而发生的现象。随着细胞自然凋亡的分子生物学和生物化学研究的深入,对以动物细胞产品生产为目的的细胞培养产业将产生极有价值的影响。采用DNA重组技术把预防细胞自然凋亡的基因导入细胞和在培基中加入具有抗细胞自然凋亡的化合物等手段已用于预防或减缓细胞培养过程中的细胞自然凋亡。这些技术将大大延长细胞达到饱和密度后的培养时间,从而使细胞培养系统的生产效率得以显著提高。     

Biochemical analysis of programmed cell death during premeiotic stages of spermatogenesis in vivo and in vitro

Control points of regulator action during spermatogenesis are not completely known. Using the shark testis model, which facilitates analysis of spermatogenesis stage-by-stage in vivo and in vitro, an early biochemical marker of programmed cell death (PCD) was detected. Nucleosomal oligomers were seen in DNA extracts of testis and isolated spermatocysts (clonal germ cell/ Sertoli cell units) at premeiotic (PrM), but not meiotic (M) or postmeiotic (PoM), stages. Cell nuclei isolated from M stages of development were susceptible to cleavage by micrococcal nuclease, suggesting that developmental control of factors other than a nuclease-insensitive chromatin structure may account for stage specificity. Cytological features of apoptosis were seen in germ cells, but not Sertoli cells, of a subset of isolated PrM spermatocysts and appeared to be all-or-none in affected clones. In culture, DNA fragmentation occurred on schedule with or without various additives, but the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) decreased accumulation of DNA breakdown products. Identification of the apoptotic form of PCD as a major, variable component of normal spermatogenesis and the use of PrM spermatocysts as an in vitro test system will allow further definition of mechanisms and developmental and physiological controls. © 1995 Wiley-Liss, Inc.     

坏死性凋亡:一种新的细胞死亡方式

传统上,细胞死亡分为凋亡和坏死两类。而近年来越来越多的研究表明坏死性凋亡是一种不同于凋亡和坏死的新型细胞死亡途径,在多种疾病模型中发挥着重要作用。本文对坏死性凋亡的产生机制、坏死性凋亡同凋亡和坏死的区别及其在疾病和药物靶点发现中的作用进行综述,以利于加深对不同细胞死亡方式的认识并促进相关新药的研发。     

Active participation of cell death in development and organismal homeostasis

The precise, regional execution of programmed cell death is required for the proper patterning and sculpting of the embryonic primordium during animal development. In addition, cell death that is not directly involved in sculpting is also widely observed. The most abundant morphological form of programmed cell death in developing animals is apoptosis, and identification of the apoptotic genetic pathways has enabled the study of apoptosis' regulation and roles during development. Genetic and bio-imaging studies have permitted the study of the active roles of cell death in development and organismal homeostasis.     

昆虫细胞程序性死亡的研究进展

在昆虫发育和抵抗病原微生物的入侵过程中,细胞凋亡与自噬性死亡现象十分常见。昆虫细胞凋亡的研究已经取得了许多的成果,但是有关细胞自噬程序性死亡的研究还正在深入。昆虫细胞凋亡的信号通路至少有3条：一条类似于线虫细胞的凋亡信号通路,另一条类似于哺乳动物细胞的凋亡信号通路, 还有一条不依赖于胱天蛋白酶的凋亡信号通路。在昆虫的多种组织细胞中,细胞凋亡与自噬程序性死亡在信号通路上存在互串(cross talking),可以相互促进、抑制或替代。了解昆虫细胞程序性死亡对防治害虫具有一定的意义。     

Biochemical characterization of programmed cell death in NGF-deprived sympathetic neurons

Young sympathetic neurons die when deprived of nerve growth factor (NGF). Under such circumstances, cell death is appropriate to the developing nervous system and requires RNA and protein synthesis. We have hypothesized the existence of an endogenous death program within neurons that is suppressed by trophic factors. The extent and timing of required changes in the synthetic events that comprise the death program are unknown. In an effort to characterize the biochemical events that mediate the death program further, we performed several experiments on embryonic rat sympathetic neurons in vitro. The death program was blocked with cycloheximide when total protein synthesis was inhibited ≥80%. When protein synthesis was inhibited within 22 ± 4 h of NGF deprivation, death was prevented in half the neurons. Hence, we define the commitment point for protein synthesis to be 22 ± 4 h. Analogously, the commitment point for RNA synthesis was 26 ± 4 h and that for NGF rescue, 24 ± 4 h. We tested the ability of a wide variety of chemicals to interfere with the death program. Most compounds tested were unable to prevent neuronal death. Some treatments, however, did save NGF-deprived neurons and were subsequently characterized. These included ultraviolet light and agents that raise intracellular concentrations of cAMP. Finally, we looked for the neuronal expression in vitro and in vivo of genes that have been associated with programmed death in other cell types, including TRPM-2/SGP-2, polyubiquitin, TGFβ-1, c-fos, and c-myc. None of these genes showed significant activation associated with neuronal death. © 1992 John Wiley & Sons, Inc.     

Gene-dependent cell death in yeast

Caspase-dependent apoptotic cell death has been extensively studied in cultured cells and during embryonic development, but the existence of analogous molecular pathways in single-cell species is uncertain. This has reduced enthusiasm for applying the advanced genetic tools available for yeast to study cell death regulation. However, partial characterization in mammals of additional genetically encoded cell death mechanisms, which lead to a range of dying cell morphologies and necrosis, suggests potential applications for yeast genetics. In this light, we revisited the topic of gene-dependent cell death in yeast to determine the prevalence of yeast genes with the capacity to contribute to cell-autonomous death. We developed a rigorous strategy by allowing sufficient time for gene-dependent events to occur, but insufficient time to evolve new populations, and applied this strategy to the Saccharomyces cerevisiae gene knockout collection. Unlike sudden heat shock, a ramped heat stimulus delivered over several minutes with a thermocycler, coupled with assessment of viability by automated counting of microscopic colonies revealed highly reproducible gene-specific survival phenotypes, which typically persist under alternative conditions. Unexpectedly, we identified over 800 yeast knockout strains that exhibit significantly increased survival following insult, implying that these genes can contribute to cell death. Although these death mechanisms are yet uncharacterized, this study facilitates further exploration.     

巨噬细胞的激活诱导死亡

淋巴细胞的激活诱导细胞死亡(AICD)的分子机制已经得到了广泛的研究。巨噬细胞中也存在AICD,但是诱导巨噬细胞AICD的分子机理仍不是很清楚。最近,一些研究表明zVAD或IFNγ通过提高MEF2C蛋白稳定性,从而增加其在巨噬细胞中的含量。MEF2C和TLR2、4信号通路一起,诱导了Nur77的表达。Nur77的表达介导了巨噬细胞的凋亡。LPS激活的ERK和p38是诱导Nur77表达和细胞凋亡所必需的。p38/STAT1/ROS途径也介导了巨噬细胞的AICD。撤除血清诱导的巨噬细胞凋亡可能是一种新的巨噬细胞AICD模型。这些发现将有助于我们对巨噬细胞AICD的进一步了解。     

Programmed cell death: alive and well in the new millennium

Research performed over the past decade has transformed apoptosis from a distinctive form of cell death known only by its characteristic morphology and genomic destruction to an increasingly well understood cellular disassembly pathway remarkable for its complex and multifaceted regulation. Here, we summarize current understanding of apoptotic events, note recent advances in this field and identify questions that might help guide research in the coming years.     

Programmed cell death in cereal aleurone

Progress in understanding programmed cell death (PCD) in the cereal aleurone is described. Cereal aleurone cells are specialized endosperm cells that function to synthesize and secrete hydrolytic enzymes that break down reserves in the starchy endosperm. Unlike the cells of the starchy endosperm, aleurone cells are viable in mature grain but undergo PCD when germination is triggered or when isolated aleurone layers or protoplasts are incubated in gibberellic acid (GA). Abscisic acid (ABA) slows down the process of aleurone cell death and isolated aleurone protoplasts can be kept alive in media containing ABA for up to 6 months. Cell death in barley aleurone occurs only after cells become highly vacuolated and is manifested in an abrupt loss of plasma membrane integrity. Aleurone cell death does not follow the apoptotic pathway found in many animal cells. The hallmarks of apoptosis, including internucleosomal DNA cleavage, plasma membrane and nuclear blebbing and formation of apoptotic bodies, are not observed in dying aleurone cells. PCD in barley aleurone cells is accompanied by the accumulation of a spectrum of nuclease and protease activities and the loss of organelles as a result of cellular autolysis.     

Erucylphosphocholine-induced apoptosis in glioma cells: involvement of death receptor signalling and caspase activation

Erucylphosphocholine (ErPC) is a promising anti-neoplastic drug for the treatment of malignant brain tumours. It exerts strong anti-cancer activity in vivo and in vitro and induces apoptosis even in chemoresistant glioma cell lines. The purpose of this study was to expand on our previous observations on the potential mechanisms of ErPC-mediated apoptosis with a focus on death receptor activation and the caspase network. A172 and T98G glioma cells were treated with ErPC for up to 48 h. ErPC effects on the expression of the tumour necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL) receptor system, and on caspase activation were determined. ErPC had no effect on the expression of TNFalpha or TRAIL. Inhibition of the TNF or TRAIL signalling pathway with antagonistic antibodies or fusion proteins did not affect apoptosis induced by ErPC, and a dominant-negative FADD construct did not abolish ErPC-induced effects. Western blot analysis indicated that ErPC-triggered apoptosis resulted in a time-dependent processing of caspases-3, -7, -8 and -9 into their respective active subunits. Co-treatment of A172 cells with different caspase inhibitors prevented apoptosis but did not abrogate cell death. These data suggest that A172 cells might have an additional caspase-independent pathway that insures cell death and guarantees killing of those tumour cells whose caspase pathway is incomplete.     

氧死亡:一种新型调节性细胞死亡

氧死亡(oxeiptosis)是2018年提出的一种新的调节性细胞死亡方式(regulated cell death,RCD).其特点是活性氧诱导的Caspase非依赖性的凋亡样细胞死亡.它有自身独特的损伤诱因(活性氧)、关健基因与通路(KEAP1-PGAM5-AIFM1),不同于坏死、细胞凋亡、坏死性凋亡、焦亡、铁死...