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PubMed1998

Increased cyclin E level in retinoblastoma cells during programmed cell death.

Camptothecin (an inhibitor of topoisomerase I) and etoposide and amsacrine (inhibitors of topoisomerase II) both capable of triggering programmed cell death in Y79 cells, induced a remarkable dose-dependent increase in the level of cyclin E in these cells. Camptothecin was found to be the most effective compound. The effect was not observed when the cells were treated with other inducers of programmed cell death (C2-ceramide, sodium butyrate, interleukin-1beta and tumor necrosis factor), all of which do not damage DNA. The effect, which was completely prevented by inhibitors of macromolecular synthesis, occurred after a lag phase (12 hrs.) and increased concurrently with the rise in programmed cell death (PCD), reaching a maximum after 36 hrs. of incubation, when a large percentage of cells (95%) showed clear PCD signals. We suggest that cyclin E takes part in the final stage of programmed cell death which is induced by topoisomerase inhibitors in Y79 cells.

Amsacrine↗
PubMed1993

The implications of a unified theory of programmed cell death, polyamines, oxyradicals and histogenesis in the embryo.

Programmed cell death (apoptosis) is the ubiquitous biological phenomenon of intentional cell death that eliminates redundant cells, changes phenotypic composition during histogenesis, provides form during morphogenesis and balances mitosis in renewing tissues. This form of cell death is controlled by a genetic program(s) that kills the targeted cell without causing subsequent inflammation. Malignant cells implanted into the appropriate regulatory field in the embryo will lose their malignant phenotype yet retain the capacity for proliferation and differentiation. This embryonic regulation of cancer requires simultaneous contact with specific structures on the surfaces of normal cells and exposure to soluble, extracellular signals. During studies to identify such soluble factors in the blastocyst, extracellular hydrogen peroxide was discovered in the blastocele fluid. Current evidence indicates that this hydrogen peroxide causes apoptosis of inner cell mass cells destined to develop into trophectoderm--the first apoptotic event during mammalian development which likely prevents the formation of ectopic trophectoderm in the soon-to-appear germ layers (histogenesis). The evidence also suggests that the hydrogen peroxide is generated during the oxidation of extracellular polyamines by a family of enzymes called amine oxidases. The components of this mechanism are also present in the mammalian epidermis, where they are proposed to control the survival of basal cell progeny and hence epidermal homeostasis (essentially controlling the production of tissue mass). This mechanism causes not only apoptosis in vivo, but also the unwanted and artefactual cell death in vitro known as the crisis of spontaneous transformation. These data suggest a novel link between polyamines and apoptosis, a link that has practical as well as theoretical implications.(ABSTRACT TRUNCATED AT 250 WORDS)

Amine Oxidase (Copper-Containing)↗
PubMed1999

Antisense bcl-2 treatment increases programmed cell death in non-small cell lung cancer cell lines.

Programmed cell death (PCD) is a genetically regulated pathway that is altered in many cancers. This process is, in part, regulated by the ratio of PCD inducers (Bax) or inhibitors (Bcl-2). An abnormally high ratio of Bcl-2 to Bax prevents PCD, thus contributing to resistance to chemotherapeutic agents, many of which are capable of inducing PCD. Non-small cell lung cancer (NSCLC) cells demonstrate resistance to these PCD-inducing agents. If Bcl-2 prevents NSCLC cells from entering the PCD pathway, then reducing the amount of endogenous Bcl-2 product may allow these cells to spontaneously enter the PCD pathway. Our purpose was to determine the effects of bcl-2 antisense treatment on the levels of programmed cell death in NSCLC cells. First, we determined whether bcl-2 and bax mRNA were expressed in three morphologically distinct NSCLC cell lines: NCI-H226 (squamous), NCI-H358 (adenocarcinoma), and NCI-H596 (adenosquamous). Cells were then exposed to synthetic antisense bcl-2 oligonucleotide treatment, after which programmed cell death was determined, as evidenced by DNA fragmentation. Bcl-2 protein expression was detected immunohistochemically. All three NSCLC cell lines expressed both bcl-2 and bax mRNA and had functional PCD pathways. Synthetic antisense bcl-2 oligonucleotide treatment resulted in decreased Bcl-2 levels, reduced cell proliferation, decreased cell viability, and increased levels of spontaneous PCD. This represents the first evidence that decreasing Bcl-2 in three morphologically distinct NSCLC cell lines allows the cells to spontaneously enter a PCD pathway. It also indicates the potential therapeutic use of antisense bcl-2 in the treatment of NSCLC.

Adenocarcinoma↗
PubMed1995

FK506 augments activation-induced programmed cell death of T lymphocytes in vivo.

FK506 is an immunosuppressive drug that inhibits T cell receptor-mediated signal transduction. This drug can induce immunological tolerance in allograft recipients. In this study, we investigated the in vivo effects of FK506 on T cell receptor-mediated apoptosis induction. Injection of anti-CD3 antibody (Ab) in mice resulted in the elimination of CD4+ CD8+ thymocytes by DNA fragmentation. FK506 treatment significantly augmented thymic apoptosis induced by in vivo anti-CD3 Ab administration. Increased thymic apoptosis resulted in the disappearance of CD4+ CD8+ thymocytes after anti-CD3 Ab/FK506 treatment. DNA fragmentation triggered by FK506 was induced exclusively in antigen-stimulated T cells, since enhanced DNA fragmentation induced by in vivo staphylococcal enterotoxin B (SEB) injection was confirmed in SEB-reactive V beta 8+ thymocytes but not in SEB-nonreactive V beta 6+ thymocytes. In addition to thymocytes, mature peripheral T cells also die by activation-induced programmed cell death. A similar effect of FK506 on activation-induced programmed cell death was observed in SEB-activated peripheral spleen T cells. In contrast, cyclosporin A treatment did not enhance activation-induced programmed cell death of thymocytes and peripheral T cells. Apoptosis is required for the generation and maintenance of self-tolerance in the immune system. Our findings suggest that FK506-triggered apoptosis after elimination of antigen-activated T cells may represent a potential mechanism of the immunological tolerance achieved by FK506 treatment.

Animals↗
PubMed2006

Comparative microarray analysis of programmed cell death induced by proteasome malfunction and hypersensitive response in plants.

Programmed cell death (PCD) plays a pivotal role in the elimination of injured or unwanted cells during diverse physiological and developmental conditions in organisms. However in contrast to the animal system, signaling pathways and molecular mechanism of PCD are largely unknown in plants. We previously reported that silencing of NbPAF encoding the alpha6 subunit of 20S proteasome by virus-induced gene silencing activated programmed cell death in plants by inactivating proteasome function. In this study, we analyzed global gene expression profile of PCD induced by suppression of NbPAF expression, in comparison with that of hypersensitive response (HR)-induced PCD, using a cDNA microarray representing 4685 hot pepper genes. HR is a well-characterized PCD program in plants, which occurs in response to pathogen infection. The microarray analyses identified 247 genes whose gene expression was differentially modulated during PCD activated by NbPAF depletion or HR. Most of the genes that were up-regulated during the NbPAF-mediated PCD, including the ubiquitin/proteasome pathway-related genes, were down-regulated during HR cell death. In contrast, transcription of many defense-related genes, transcription factor genes, and photosynthesis-related genes remained unchanged or repressed during NbPAF-mediated PCD, while it was highly induced during HR cell death. Only a small number of genes including antioxidant-related genes and proteases were found to be up-regulated during induction of PCD by both proteasome inactivation and HR. Based on these results, these two PCD pathways appear to be differentially regulated, but some overlapping mechanism exists, which involves core regulators of plant PCD.

Apoptosis↗
PubMed1994

Motoneurons deprived of trophic support in vitro require new gene expression to undergo programmed cell death.

During normal development, large numbers of neurons die by programmed cell death. This phenomena has been extensively studied in the lateral motor column of chick embryos, where approximately 50% of the motoneurons that are initially produced, subsequently die due in part to competition for a limited supply of target-derived trophic support. Inhibitors of RNA and protein synthesis block this cell loss in vivo, indicating a requirement for new gene expression (Oppenheim et al., 1990). Prior to their commitment to death, motoneurons can be isolated as a relatively pure population from chick spinal cord for in vitro study. Cells plated with muscle extract, a potent source of target-derived trophic support, survive, and have large, phase-bright cell bodies and extensive neurite outgrowth. In contrast, motoneurons cultured in the absence of muscle extract die within 48 h. This death can be blocked by the RNA synthesis inhibitor actinomycin D, at the time when the cells become committed to die, suggesting that new gene expression is required for cell death. DNA fragmentation and nuclear condensation indicate that some of these cells die by apoptosis. Therefore, it appears that many aspects of motoneuron development observed in vivo can be reconstituted in vitro. These cultures can be used as a model system for studying neuronal death and may contribute to an understanding of the molecular mechanisms that mediate programmed cell death during neuronal development.

Animals↗
PubMed2000

Programmed cell death in the developing somites is promoted by nerve growth factor via its p75(NTR) receptor.

Neurotrophins control neuron number during development by promoting the generation and survival of neurons and by regulating programmed neuronal death. In the latter case, the cell death induced by nerve growth factor (NGF) in the developing chick retina is mediated by p75(NTR), the common neurotrophin receptor (J. M. Frade, A. Rodriguez-Tebar, and Y.-A. Barde, 1996, Nature 383, 166-168). Here we show that NGF also induces the programmed death of paraxial mesoderm cells in the developing somites. Both NGF and p75(NTR) are expressed in the somites of chick embryos at the time and the place of programmed cell death. Moreover, neutralizing the activity of endogenous NGF with a specific blocking antibody, or antagonizing NGF binding to p75(NTR) by the application of human NT-4/5, reduces the levels of apoptotic cell death in both the sclerotome and the dermamyotome by about 50 and 70%, respectively. Previous data have shown that Sonic hedgehog is necessary for the survival of differentiated somite cells. Consistent with this, Sonic hedgehog induces a decrease of NGF mRNA in somite explant cultures, thus showing the antagonistic effect of NGF and Sonic hedgehog with respect to somite cell survival. The regulation of programmed cell death by NGF/p75(NTR) in a mesoderm-derived tissue demonstrates the capacity of neurotrophins and their receptors to influence critical developmental processes both within and outside of the nervous system.

Animals↗
PubMed1993

Do all programmed cell deaths occur via apoptosis?

During development, large numbers of cells die by a nonpathological process referred to as programmed cell death. In many tissues, dying cells display similar changes in morphology and chromosomal DNA organization, which has been termed apoptosis. Apoptosis is such a widely documented phenomenon that many authors have assumed all programmed cell deaths occur by this process. Two well-characterized model systems for programmed cell death are (i) the death of T cells during negative selection in the mouse thymus and (ii) the loss of intersegmental muscles of the moth Manduca sexta at the end of metamorphosis. In this report we compare the patterns of cell death displayed by T cells and the intersegmental muscles and find that they differ in terms of cell-surface morphology, nuclear ultrastructure, DNA fragmentation, and polyubiquitin gene expression. Unlike the T cells, which are known to die via apoptosis, we find that the intersegmental muscles display few of the features that characterize apoptosis. These data suggest that more than one cell death mechanism is used during development.

Animals↗
PubMed2003

Multiple mediators of plant programmed cell death: interplay of conserved cell death mechanisms and plant-specific regulators.

Programmed cell death (PCD) is a process aimed at the removal of redundant, misplaced, or damaged cells and it is essential to the development and maintenance of multicellular organisms. In contrast to the relatively well-described cell death pathway in animals, often referred to as apoptosis, mechanisms and regulation of plant PCD are still ill-defined. Several morphological and biochemical similarities between apoptosis and plant PCD have been described, including DNA laddering, caspase-like proteolytic activity, and cytochrome c release from mitochondria. Reactive oxygen species (ROS) have emerged as important signals in the activation of plant PCD. In addition, several plant hormones may exert their respective effects on plant PCD through the regulation of ROS accumulation. The possible plant PCD regulators discussed in this review are integrated in a model that combines plant-specific regulators with mechanisms functionally conserved between animals and plants.

Apoptosis↗
PubMed2003

A tomato metacaspase gene is upregulated during programmed cell death in Botrytis cinerea-infected leaves.

Programmed cell death (PCD) in plant cells is often accompanied by biochemical and morphological hallmarks similar to those of animal apoptosis. However, orthologs of animal caspases, cysteinyl aspartate-specific proteases that constitute the core component of animal apoptosis, have not yet been identified in plants. Recent studies have revealed the presence of a family of genes encoding proteins with distant homology to mammalian caspases, designated metacaspases, in the Arabidopsis thaliana genome. Here, we describe the isolation of LeMCA1, a type-II metacaspase cDNA clone from tomato (Lycopersicon esculentum Mill.). BLAST analysis demonstrated that the LeMCA1 gene is located in close vicinity of several genes that have been linked with PCD. Southern analysis indicated the existence of at least one more metacaspase in the tomato genome. LeMCA1 mRNA levels rapidly increased upon infection of tomato leaves with Botrytis cinerea, a fungal pathogen that induces cell death in several plant species. LeMCA1 was not upregulated during chemical-induced PCD in suspension-cultured tomato cells.

Apoptosis↗
PubMed2005

Programmed cell death via mitochondria: different modes of dying.

Programmed cell death (PCD) is a major component of normal development, preservation of tissue homeostasis, and elimination of damaged cells. Many studies have subdivided PCD into the three categories of apoptosis, autophagy, and necrosis based on criteria such as morphological alterations, initiating death signal, or the implication of caspases. However, these classifications fail to address the interplay between the three types of PCD. In this review, we will discuss the central role of the mitochondrion in the integration of the cell death pathways. Mitochondrial alterations such as the release of sequestered apoptogenic proteins, loss of transmembrane potential, production of reactive oxygen species (ROS), disruption of the electron transport chain, and decreases in ATP synthesis have been shown to be involved in, and possibly responsible for, the different manifestations of cell death. Thus, the mitochondria can be viewed as a central regulator of the decision between cellular survival and demise.

Adenosine Triphosphate↗
PubMed2005

Programmed cell death in the germline.

In many organisms, programmed cell death of germ cells is required for normal development. This often occurs through highly conserved events including the transfer of vital cellular material to the growing gametes following death of neighboring cells. Germline cell death also plays a role in such diverse processes as removal of abnormal or superfluous cells at certain checkpoints, establishment of caste differentiation, and individualization of gametes. This review focuses on the cell death events that occur during gametogenesis in both vertebrates and invertebrates. It also examines the signals and machinery that initiate and carry out these germ cell deaths.

Animals↗
PubMed2002

Developmental programmed cell death in plants.

Mechanisms of plant developmental programmed cell death (PCD) have been intensively studied in recent years. Most plant developmental PCD is triggered by plant hormones, and the 'death signal' may be transduced by hormonal signaling pathways. Although there are some fundamental differences in the regulation of developmental PCD in various eukaryotes of different kingdoms, hormonal control and death signal transduction via pleiotropic signaling pathways constitute a common framework. However, plants possess a unique process of PCD execution that depends on vacuolar lytic function. Comparisons of the developmental PCD mechanisms of plants and other organisms are providing important insights into the detailed characteristics of developmental PCD in plants.

Apoptosis↗
PubMed2000

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.

Apoptosis↗
PubMed1995

Programmed cell death enhances uniformity in rat cerebral hemispheres.

Programmed cell death (apoptosis) in rat cerebral hemispheres (CH) reportedly occurs around postnatal day 7 and kills 15-75% of all cells whose continuing presence would be of disadvantage for the organism: neurons erroneously connected, or supranumerary neurons that do not find targets and are not protected by neurotrophins. In the present paper we report that apoptosis (or a concomitant phenomenon) reduces also variability (coefficient of variation, CV) of CH parameters: weight, DNA content and protein content (presented here as a percent of the mean of each of these parameters). Postapoptotic brains have significantly lower CV of these parameters than the preapoptotic brains. Presumably, this trend toward uniformity offers selective advantages (for rat) and established itself during evolution. The mechanisms and the control of this phenomenon are at present largely unknown.

Animals↗
PubMed2000

A comparison of programmed cell death between species.

Key components of the programmed cell death pathway are conserved between Caenorhabditis elegans, Drosophila melanogaster and humans. The search for additional homologs has been facilitated by the availability of the entire genomic sequence for each of these organisms.

Animals↗
PubMed2003

The role of Apaf-1 in programmed cell death: from worm to tumor.

Apoptosis or programmed cell death is an important process to eliminate unnecessary or hazardous cells. Apaf-1, a mammalian homologue of CED-4 of C. elegans, is the essential adaptor molecule in the mitochondrial pathway of apoptosis. Mice lacking Apaf-1 show accumulation of neurons in the developing central nervous system due to reduced apoptosis. Apaf-1-deficient cells are remarkably resistant to various apoptotic stimuli. Apaf-1-mediated apoptosis plays a role in the prevention of tumorigenesis. However, Apaf-1-independent cell death pathways are also indicated. In this review, we will summarize what has been learned about the role of Apaf-1 by biochemical and genetical approaches.

Animals↗
PubMed2002

[Programmed cell death: molecular mechanisms and detection].

Apoptosis or programmed cell death is genetically determined process to destroy cells for the maintaining of cellular homeostasis in the tissue. This paper reviews the current knowledge on the molecular mechanisms of apoptosis. Activation of cysteine proteases called caspases plays a major role in the execution of apoptosis. These activated caspases selectively cleave cellular proteins, which result in apoptotic morphology (internucleosomal fragmentation of DNA into 180-200 base pair pieces, shrinkage of the cell and the nucleus as well and fragmentation of the cell into apoptotic bodies) and death of the cell. Now two pathways of caspase activation are reported. The first through triggering of cellular death-receptor superfamily. The second is mitochondrial pathway induced by the changes of the expression of pro- and anti-apoptotic genes in the cell. It leads to release of cytochrome c and apoptosis inducing factor from mitochondria. The paper reviews also currently used methods of detection of apoptotic cells in tissue samples, causes of false-positive or false-negative results of ISEL and TUNEL in situ reactions.

Aortic Aneurysm, Thoracic↗