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PubMed2004

Programmed cell deaths. Apoptosis and alternative deathstyles.

Programmed cell death is a major component of both normal development and disease. The roles of cell death during either embryogenesis or pathogenesis, the signals that modulate this event, and the mechanisms of cell demise are the major subjects that drive research in this field. Increasing evidence obtained both in vitro and in vivo supports the hypothesis that a variety of cell death programs may be triggered in distinct circumstances. Contrary to the view that caspase-mediated apoptosis represents the standard programmed cell death, recent studies indicate that an apoptotic morphology can be produced independent of caspases, that autophagic execution pathways of cell death may be engaged without either the involvement of caspases or morphological signs of apoptosis, and that even the necrotic morphology of cell death may be consistently produced in some cases, including certain plants. Alternative cell death programs may imply novel therapeutic targets, with important consequences for attempts to treat diseases associated with disregulated programmed cell death.

Animals↗
PubMed1998

Reactive oxygen species participate in the control of mouse embryonic cell death.

Programmed cell death or apoptosis is an essential process during the morphogenesis of a large number of structures. Evidence obtained over the past few years indicates that, in some cases, the generation of reactive oxygen species (ROS) is an important event during the course of apoptosis. Using an in vitro culture system in which digit individualization of developing limbs normally occurs, we assayed the effect of different antioxidants on the cell death that takes place at interdigits. The addition of phenol, dimethyl sulfoxide, or 2',7'-dichlorodihydrofluorescein diacetate (DCDHF-DA) to murine developing limbs in culture prevented digit individualization as well as the typical interdigital cell death. Two ROS-sensitive dyes, 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide and DCDHF-DA, stained interdigits and the so-called "necrotic zones," implying that they contain cells under oxidative stress. Very few interdigital cells were doubly stained with the ROS probes and two cell death indicators (i.e., acridine orange and propidium iodide), suggesting that they detect a different stage during the course of apoptosis. Furthermore, we found cells stained for ROS that did not express a specific macrophage marker and in a few cases were seen surrounded by a macrophage. Surprisingly, many regions of the midgestation mouse embryo that are undergoing cell death correlated with those that have a markedly higher level of ROS. Our data suggest that the generation of oxidative stress is a common requirement for cell death that occurs during mouse embryonic development.

Animals↗
PubMed2006

A cellular suicide strategy of plants: vacuole-mediated cell death.

Programmed cell death (PCD) occurs in animals and plants under various stresses and during development. Recently, vacuolar processing enzyme (VPE) was identified as an executioner of plant PCD. VPE is a cysteine protease that cleaves a peptide bond at the C-terminal side of asparagine and aspartic acid. VPE exhibited enzymatic properties similar to that of a caspase, which is a cysteine protease that mediates the PCD pathway in animals, although there is limited sequence identity between the two enzymes. VPE and caspase-1 share several structural properties: the catalytic dyads and three amino acids forming the substrate pockets (Asp pocket) are conserved between VPE and caspase-1. In contrast to such similarities, subcellular localizations of these proteases are completely different from each other. VPE is localized in the vacuoles, while caspases are localized in the cytosol. VPE functions as a key molecule of plant PCD through disrupting the vacuole in pathogenesis and development. Cell death triggered by vacuolar collapse is unique to plants and has not been seen in animals. Plants might have evolved a VPE-mediated vacuolar system as a cellular suicide strategy.

Amino Acid Sequence↗
PubMed2004

Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death.

Programmed cell death (PCD) is essential for normal development and maintenance of tissue homeostasis in multicellular organisms. While it is now evident that PCD can take many different forms, apoptosis is probably the most well-defined cell death programme. The characteristic morphological and biochemical features associated with this highly regulated form of cell death have until recently been exclusively attributed to the caspase family of cysteine proteases. As a result, many investigators affiliate apoptosis with its pivotal execution system, i.e. caspase activation. However, it is becoming increasingly clear that PCD or apoptosis can also proceed in a caspase-independent manner and maintain key characteristics of apoptosis. Mitochondrial integrity is central to both caspase-dependent and-independent cell death. The release of pro-apoptotic factors from the mitochondrial intermembrane space is a key event in a cell's commitment to die and is under the tight regulation of the Bcl-2 family. However, the underlying mechanisms governing the efflux of these pro-death molecules are largely unknown. This review will focus on the regulation of mitochondrial integrity by Bcl-2 family members with particular attention to the controlled release of factors involved in caspase-independent cell death.

Animals↗
PubMed2004

MicroRNAs and the regulation of cell death.

Programmed cell death, or apoptosis, is ubiquitous, both during development and in the adult. Many components of the evolutionarily conserved machinery that brings about and regulates cell death have been identified, and all of these are proteins. However, in the past three years it has become clear that roughly 1% of predicted genes in animals encode small noncoding RNAs known as microRNAs, which regulate gene function. Here we review the recent identification of microRNA cell death regulators in Drosophila, hints that such regulators are also likely to exist in mammals, and more generally the approaches and tools that are now available to probe roles for noncoding RNAs in the control of cell death.

Animals↗
PubMed2002

Caspase cleavage of the transcription factor FLI-1 during preB leukemic cell death.

Programmed cell death (apoptosis) is a complex phenomenon that is mediated in mammals mainly via the selective cleavage of intracellular proteins by the large family of cysteine aspartate protease caspases. Apoptosis is tightly regulated by the competitive effect of numerous proteins displaying either pro-apoptotic or anti-apoptotic activity. The ETS-family transcription factor FLI-1, frequently associated with malignant transformation, has been shown to display anti-apoptotic activity in several cell types including avian erythroblasts, mouse fibroblasts or lymphoid cells. We show here that apoptosis of murine preB leukemic cells is accompanied with the specific cleavage of FLI-1 by a caspase-like activity. We also demonstrate that the two isoforms of FLI-1 are indeed cleaved at three conserved sites by caspase 3 in vitro. The conservation of these cleavage sites among species suggests that the caspase cleavage of the anti-apoptotic transcription factor FLI-1 may represent a critical step to ensure irreversible cell death.

Animals↗
PubMed2003

A SAGE approach to discovery of genes involved in autophagic cell death.

Programmed cell death (PCD), important in normal animal physiology and disease, can be divided into at least two morphological subtypes, including type I, or apoptosis, and type II, or autophagic cell death. While many molecules involved in apoptosis have been discovered and studied intensively during the past decade, autophagic cell death is not well characterized molecularly. Here we report the first comprehensive identification of molecules associated with autophagic cell death during normal metazoan development in vivo. During Drosophila metamorphosis, the larval salivary glands undergo autophagic cell death regulated by a hormonally induced transcriptional cascade. To identify and analyze the genes expressed, we examined wild-type patterns of gene expression in three predeath stages of Drosophila salivary glands using serial analysis of gene expression (SAGE) [7]. 1244 transcripts, including genes involved in autophagy, defense response, cytoskeleton remodeling, noncaspase proteolysis, and apoptosis, were expressed differentially prior to salivary gland death. Mutant expression analysis indicated that several of these genes were regulated by E93, a gene required for salivary gland cell death. Our analyses strongly support both the emerging notion that there is overlap with respect to the molecules involved in autophagic cell death and apoptosis, and that there are important differences.

Animals↗
PubMed2002

SLUGging away at cell death.

Programmed cell death (PCD) plays an important role in normal and malignant hematopoieis. In this issue of Cancer Cell, Inoue et al. (2002) demonstrate that the CED-1 homolog, Slug, is a key regulator of apoptosis in the response of early hematopoietic progenitors to gamma radiation.

Animals↗
PubMed1998

An insertional mutagenesis approach to Dictyostelium cell death.

Programmed cell death (PCD) in Dictyostelium shows a pattern of ordered degeneration similar to that observed in higher eukaryotes but somewhat different from the most studied form of PCD, i.e. apoptosis. To contribute to a genetic definition of this process, Dictyostelium HMX44A cells have been subjected to insertional mutagenesis, followed by selection based on several rounds of differentiation/regrowth to recover only cells resistant to death. We describe here the approach used, a partial characterization of the first mutant thus obtained called C5 showing some dissociation of cell death signs, and, in this case where plasmid rescue was not possible, as a first step towards identification of the gene at play recovery of genomic flanking sequences via genomic recircularization and PCR. This work demonstrates the feasibility of an insertional mutagenesis approach to obtain death-resistant mutants in Dictyostelium.

Animals↗
PubMed1999

LFG: an anti-apoptotic gene that provides protection from Fas-mediated cell death.

Programmed cell death regulates a number of biological phenomena, and the apoptotic signal must itself be tightly controlled to avoid inappropriate cell death. We established a genetic screen to search for molecules that inhibit the apoptotic signal from the Fas receptor. Here we report the isolation of a gene, LFG, that protects cells uniquely from Fas but not from the mechanistically related tumor necrosis factor alpha death signal. LFG is widely distributed, but remarkably is highly expressed in the hippocampus. LFG can bind to the Fas receptor, but does not regulate Fas expression or interfere with binding of an agonist antibody. Furthermore LFG does not inhibit binding of FADD to Fas.

Amino Acid Sequence↗
PubMed2003

Ataxia Jackson (ax(J)): a genetic model for apoptotic neuronal cell death.

Programmed cell death or apoptosis is an important process to form normal adult cytoarchitecture. But in vivo analysis of neuronal apoptosis has not been well advanced. Therefore, apoptotic cell death of a particular neuronal system or anatomical part in a mutant is an invaluable target to learn about a link between a gene and neuronal apoptosis. Ataxia (ax) is an autosomal recessive neurological mutant mouse. We recently investigated brains of homozygotes for ataxia Jackson (ax(J)), an allele of ax, using TUNEL method. A few TUNEL-positive cells were observed in the granular cell layer of the cerebellum, the dentate gyrus, and the olfactory bulb of phenotypically normal littermates (ax(J)/+ or +/+) aged at 23-38 days. In affected ax(J)/ax(J) mice, however, the number of TUNEL-positive cells was significantly increased in the cerebellum, particularly in the granular cell layer (p < 0.05). The ax(J) mouse will be an in vivo unique model for studies on the genetic basis of apoptotic neuronal cell death, and identification of the ax gene is desired to elucidate molecular basis of the apoptosis.

Animals↗
PubMed1995

Identification, characterization, and purification of a tobacco endonuclease activity induced upon hypersensitive response cell death.

Programmed cell death (pcd) is activated during the hypersensitive response (HR) of plants to avirulent pathogens. We have recently shown that, similar to pcd in animal cells, nuclei of cells undergoing HR cell death contain fragmented nuclear DNA (nDNA). Here, we report that cell death occurring during the HR is accompanied by an increase in the activity of several deoxyribonucleases. Induction of nuclease activities was coordinated with cell death and may account for the degradation of nDNA during the HR. HR-associated nuclease activities were not induced during senescence, following necrotic cell death resulting from abiotic stress, or in response to induction of plant defense mechanisms by salicylic acid. HR-associated nuclease activities were stimulated by Ca2+ and inhibited by EGTA, EDTA, and Zn2+. At least one of the HR-associated nuclease activities was detected in nuclei purified from leaves undergoing pcd. A nuclease with an electrophoretic mobility similar to that of the nuclease activity found in nuclei isolated from leaves undergoing HR cell death was purified. Our findings are in accordance with some of the biochemical events that occur during pcd in animal cells. However, further analysis of the pattern of nDNA fragmentation and the corresponding structural changes that occur in the nuclei of tobacco cells undergoing HR cell death revealed that these features may have differences from those that take place during apoptosis in animal cells.

Animals↗
PubMed2006

Arabidopsis Bax inhibitor-1 functions as an attenuator of biotic and abiotic types of cell death.

Programmed cell death (PCD) is a common process in eukaryotes during development and in response to pathogens and stress signals. Bax inihibitor-1 (BI-1) is proposed to be a cell death suppressor that is conserved in both animals and plants, but the physiological importance of BI-1 and the impact of its loss of function in plants are still unclear. In this study, we identified and characterized two independent Arabidopsis mutants with a T-DNA insertion in the AtBI1 gene. The phenotype of atbi1-1 and atbi1-2, with a C-terminal missense mutation and a gene knockout, respectively, was indistinguishable from wild-type plants under normal growth conditions. However, these two mutants exhibit accelerated progression of cell death upon infiltration of leaf tissues with a PCD-inducing fungal toxin fumonisin B1 (FB1) and increased sensitivity to heat shock-induced cell death. Under these conditions, expression of AtBI1 mRNA was up-regulated in wild-type leaves prior to the activation of cell death, suggesting that increase of AtBI1 expression is important for basal suppression of cell death progression. Over-expression of AtBI1 transgene in the two homozygous mutant backgrounds rescued the accelerated cell death phenotypes. Together, our results provide direct genetic evidence for a role of BI-1 as an attenuator for cell death progression triggered by both biotic and abiotic types of cell death signals in Arabidopsis.

Amino Acid Sequence↗
PubMed2004

A plant vacuolar protease, VPE, mediates virus-induced hypersensitive cell death.

Programmed cell death (PCD) in animals depends on caspase protease activity. Plants also exhibit PCD, for example as a response to pathogens, although a plant caspase remains elusive. Here we show that vacuolar processing enzyme (VPE) is a protease essential for a virus-induced hypersensitive response that involves PCD. VPE deficiency prevented virus-induced hypersensitive cell death in tobacco plants. VPE is structurally unrelated to caspases, although VPE has a caspase-1 activity. Thus, plants have evolved a regulated cellular suicide strategy that, unlike PCD of animals, is mediated by VPE and the cellular vacuole.

Apoptosis↗
PubMed2002

Molecular genetic control of caspases and JNK-mediated neural cell death.

Programmed cell death, or apoptosis, plays crucial roles in both development and tissue homeostasis. Apoptosis is widely observed in the nervous system during development. However, the molecular mechanisms underlying why only certain cells are selected to die and the execution of neural cell death itself are largely unknown. Recent genetic studies in mice and Drosophila revealed crucial roles for JNK (c-jun N-terminal kinase) activation in neural cell death. The JNK-mediated initiation of apoptotic mechanisms appears to be an excellent strategy for the fine-tuning of morphogenesis as well as cell selection in nervous tissue.

Animals↗
PubMed1994

Programmed cell death: necrosis versus apoptosis.

Cell death remains poorly understood, despite its obvious importance in every organ and tissue in a wide variety of biological processes, including, of course, the many pathological. The past few years have seen an amazing expansion of interest in cell death in normal development and maturation, in the pathogenesis of many acute and chronic diseases, and in the therapy of some diseases, especially malignant neoplastic diseases and some hyperplastic diseases such as psoriasis. This expansion has included an unusual interest in a supposedly new form of cell death, a "programmed cell death," designated "apoptosis." This is proposed as a hitherto undescribed form of cell death in contrast to the classical cell death, necrosis. Apoptosis is considered by some, especially by nonpathologists, to represent quite a different type of cell death. A review of the literature on on apoptosis, programmed cell death, necrosis, etc. indicates that there is no field of basic cell biology and cell pathology that is more confusing and more unintelligible than the area of apoptosis versus necrosis. If any degree of clarity is to develop in our understanding of the fundamental principles underlying cell death of any type, it is incumbent upon us to rethink "from square one" the scientific analysis of how cells die and how can we assess cell death in a reasonably rational manner.

Animals↗
PubMed1997

Death by design. Programmed cell death in cardiovascular biology and disease.

Programmed cell death (apoptosis) is recognized, increasingly, as a contributing cause of cardiac myocyte loss with ischemia/reperfusion injury, myocardial infarction, and long-standing heart failure. Although the exact mechanisms initiating apoptosis in these in vivo settings remain unproven, insights into the molecular circuitry controlling apoptosis more widely suggest the potential to protect mammalian ventricular muscle from apoptosis through one or more of these pathways, by pharmacological means or, conceivably, gene transfer.

Animals↗
PubMed1990

An organ culture system for the study of programmed cell death in the rat ventral prostate.

Glandular epithelial cells of the rat ventral prostate undergo programmed cell death in vivo following androgen ablation. Fragmentation of the prostatic DNA is an irreversible commitment step in this programmed cell death process. The amount of prostatic DNA fragmentation thus is a quantitative measure of the number of androgen-dependent prostatic glandular cells undergoing programmed death. An in vitro organ culture system was devised for determining rates of prostatic programmed cell death based upon the daily percentage of prostatic DNA fragmentation. To do this, rats were castrated and 2 weeks later treated in vivo for 3 days with exogenous androgen replacement to maximally stimulate DNA synthesis (i.e. proliferation) of the ventral prostatic glandular cells. In vitro organ cultures were established from these ventral prostates and the DNA of these explants was 125I-labeled by incubation in media containing [125I]iododeoxyuridine [( 125I]IDU). Using this in vivo-in vitro DNA labeling technique, greater than 85% of the [125I]IDU radioactivity was incorporated into DNA of the prostatic explants glandular cells. The decrease in 125I-radioactivity from prostatic explants was determined for over a 10-day period of organ culture. Using regression analysis of these data, the daily rate of programmed cell death of the glandular cells was determined. To test the validity of the method, organ cultures were maintained in media capable of inducing either necrotic (i.e. HgCl2-containing media) or programmed cell death (i.e. media lacking testosterone) and the daily decrease in the percentage of [125I]IDU retained in the tissue determined. In addition, the morphologic appearance of necrotic vs apoptotic cell death (i.e. programmed) was quantitated and compared to the [125I]IDU data. These studies demonstrated that this [125I]IDU labeled rat prostatic organ culture system can be used as an in vitro screen to quantitate the ability of various test agents to activate the programmed cell death pathway in prostatic glandular cells.

Animals↗