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PubMed1992

Inhibition of programmed cell death by cyclosporin A; preferential blocking of cell death induced by signals via TCR/CD3 complex and its mode of action.

Cyclosporin A (CsA) is reported to inhibit programmed cell death. We confirmed this by using T-cell hybridomas which are inducible to programmed cell death by activation with immobilized anti-CD3 antibody or with anti-Thy 1.2 antibody. Cell death and DNA fragmentation, characteristic features of programmed cell death, were almost completely blocked by CsA or FK506. To investigate whether CsA inhibits only the cell death through the signals via the TCR/CD3 complex or all of the programmed cell death induced by various reagents, we further established CD4+8+ thymic lymphomas which result in programmed cell death after activation with calcium ionophore, dexamethasone, cyclic AMP or anti-CD3 antibody. It was revealed that CsA could block only the cell death mediated by the TCR/CD3 complex. For the clarification of the site of action of CsA, Ca2+ influx and endocytosis of receptors after stimulation with anti-CD3 antibody were monitored in the presence of CsA, and no significant effects of CsA were observed. Furthermore, prevention of cell death was examined by adding CsA at various periods of time after initiation of culture. CsA was found to exert its effect even when added after 4 h of cultivation, and the kinetic pattern of suppression was similar to that of the suppressive effect on IL-2 production. These observations indicate that in the events of programmed cell death, the major site of action of CsA will not be the inhibition of the immediate membrane events after activation of the TCR/CD3 complex but rather the interference in the function of molecules that transmit signals between membrane events and the activation of genes in the nucleus.

Animals↗
PubMed1998

Local induction of patterning and programmed cell death in the developing Drosophila retina.

Local cell signaling can pattern the nervous system by directing cell fates, including programmed cell death. In the developing Drosophila retina, programmed cell death is used to remove excess cells between ommatidia. Cell ablation revealed the source and position of signals required for regulating the pattern of programmed cell death among these interommatidial cells. Two types of signals regulate this patterning event. Notch-mediated signals between interommatidial precursors result in removal of unneeded cells. Cone cells and primary pigment cells oppose this signal by supplying a 'life'-promoting activity; evidence is provided that this signal occurs through localized activation of the EGF Receptor/Ras pathway. Together, these signals refine the highly regular pattern observed in the adult retina.

Animals↗
PubMed2000

An alternative, nonapoptotic form of programmed cell death.

The term apoptosis often has been used interchangeably with the term programmed cell death. Here we describe a form of programmed cell death that is distinct from apoptosis by the criteria of morphology, biochemistry, and response to apoptosis inhibitors. Morphologically, this alternative form of programmed cell death appears during development and in some cases of neurodegeneration. Despite its lack of response to caspase inhibitors and Bcl-x(L), we show that this form of cell death is driven by an alternative caspase-9 activity that is Apaf-1-independent. Characterization of this alternative form of programmed cell death should lead to new insight into cell death programs and their roles in development and degeneration.

Apoptosis↗
PubMed2001

Phagocytosis promotes programmed cell death in C. elegans.

In the nematode Caenorhabditis elegans programmed cell death requires the killer genes egl-1, ced-4 and ced-3 (refs 1 and 2), and the engulfment of dying cells requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 (refs 3,4,5). Here we show that engulfment promotes programmed cell death. Mutations that cause partial loss of function of killer genes allow the survival of some cells that are programmed to die, and mutations in engulfment genes enhance the frequency of this cell survival. Furthermore, mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die. Engulfment genes probably act in engulfing cells to promote death, as the expression in engulfing cells of ced-1, which encodes a receptor that recognizes cell corpses, rescues the cell-killing defects of ced-1 mutants. We propose that engulfing cells act to ensure that cells triggered to undergo programmed cell death by the CED-3 caspase die rather than recover after the initial stages of death.

Animals↗
PubMed1996

Mitochondria and programmed cell death: back to the future.

Programmed cell death, or apoptosis, has in the past few years undoubtedly become one of the most intensively investigated biological processes. However, fundamental questions concerning the molecular and biochemical mechanisms remain to be elucidated. The central question concerns the biochemical steps shared by the numerous death induction pathways elicited by different stimuli. Heterogeneous death signals precede a common effector phase during which cells pass a threshold of 'no return' and are engaged in a degradation phase where they acquire the typical onset of late apoptosis. Alterations in mitochondrial permeability transition linked to membrane potential disruption precede nuclear and plasma membrane changes. In vitro induction of permeability transition in isolated mitochondria provokes the release of a protein factor capable of inducing nuclear chromatin condensation and fragmentation. This permeability transition is regulated by multiple endogenous effectors, including members of the bcl-2 gene family. Inhibition of these effects prevents apoptosis.

Animals↗
PubMed2005

Protozoan programmed cell death--insights from Blastocystis deathstyles.

Programmed cell death (PCD) is an essential process in the growth and development of multicellular organisms. However, accumulating evidence indicates that unicellular eukaryotes can also undergo PCD with apoptosis-like features. The protozoan parasite Blastocystis hominis has been reported to exhibit both apoptotic and non-apoptotic features of PCD when exposed to a variety of stimuli. Recent observations of PCD pathways in Blastocystis suggest that this protozoan, as is the case with its multicellular counterparts, possesses complex cell-death mechanisms.

Animals↗
PubMed2005

Transforming growth factor-beta (TGF-beta) and programmed cell death in the vertebrate retina.

Programmed cell death (PCD) is a precisely regulated phenomenon essential for the homeostasis of multicellular organisms. Developmental systems, particularly the nervous system, have provided key observations supporting the physiological role of PCD. We have recently shown that transforming growth factor-beta (TGF-beta) plays an important role in mediating ontogenetic PCD in the nervous system. As part of the central nervous system the developing retina serves as an ideal model system for investigating apoptotic processes during neurogenesis in vivo as it is easily accessible experimentally and less complex due to its limited number of different neurons. This review summarizes data indicating a pivotal role of TGF-beta in mediating PCD in the vertebrate retina. The following topics are discussed: expression of TGF-beta isoforms and receptors in the vertebrate retina, the TGF-beta signaling pathway, functions and molecular mechanisms of PCD in the nervous system, TGF-beta-mediated retinal apoptosis in vitro and in vivo, and interactions of TGF-beta with other pro- and anti-apoptotic factors.

Animals↗
PubMed2000

Mechanisms of programmed cell death in the developing brain.

Programmed cell death (apoptosis) is an important mechanism that determines the size and shape of the vertebrate nervous system. Recent gene-targeting studies have indicated that homologs of the cell-death pathway in the nematode Caenorhabditis elegans have analogous functions in apoptosis in the developing mammalian brain. However, epistatic genetic analysis has revealed that the apoptosis of progenitor cells during early embryonic development and apoptosis of postmitotic neurons at later stage of brain development have distinct roles and mechanisms. These results provide new insight on the significance and mechanism of neural cell death in mammalian brain development.

Animals↗
PubMed2002

Salt causes ion disequilibrium-induced programmed cell death in yeast and plants.

Programmed cell death (PCD) is a fundamental cellular process conserved in metazoans, plants and yeast. Evidence is presented that salt induces PCD in yeast and plants because of an ionic, rather than osmotic, etiology. In yeast, NaCl inhibited growth and caused a time-dependent reduction in viability that was preceded by DNA fragmentation. NaCl also induced the cytological hallmarks of lysigenous-type PCD, including nuclear fragmentation, vacuolation and lysis. The human anti-apoptotic protein Bcl-2 increased salt tolerance of wild-type yeast strain and calcineurin-deficient yeast mutant (cnb1Delta) that is defective for ion homeostasis, but had no effect on the NaCl or sorbitol sensitivity of the osmotic hypersensitive hog1Delta mutant -- results that further link PCD in the response to the ion disequilibrium under salt stress. Bcl-2 suppression of cnb1Delta salt sensitivity was ENA1 (P-type ATPase gene)-dependent, due in part to transcriptional activation. Salt-induced PCD (TUNEL staining and DNA laddering) in primary roots of both Arabidopsis thaliana wild type (Col-1 gl1) and sos1 (salt overly sensitive) mutant seedlings correlated positively with treatment lethality. Wild-type plants survived salt stress levels that were lethal to sos1 plants because secondary roots were produced from the shoot/root transition zone. PCD-mediated elimination of the primary root in response to salt shock appears to be an adaptive mechanism that facilitates the production of roots more able to cope with a saline environment. Both salt-sensitive mutants of yeast (cnb1Delta) and Arabidopsis (sos1) exhibit substantially more profound PCD symptoms, indicating that salt-induced PCD is mediated by ion disequilibrium.

Adaptation, Physiological↗
PubMed1991

Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans.

After programmed cell death, a cell corpse is engulfed and quickly degraded by a neighboring cell. For degradation to occur, engulfing cells must recognize, phagocytose and digest the corpses of dying cells. Previously, three genes were known to be involved in eliminating cell corpses in the nematode Caenorhabditis elegans: ced-1, ced-2 and nuc-1. We have identified five new genes that play a role in this process: ced-5, ced-6, ced-7, ced-8 and ced-10. Electron microscopic studies reveal that mutations in each of these genes prevent engulfment, indicating that these genes are needed either for the recognition of corpses by other cells or for the initiation of phagocytosis. Based upon our study of double mutants, these genes can be divided into two sets. Animals with mutations in only one of these sets of genes have relatively few unengulfed cell corpses. By contrast, animals with mutations in both sets of genes have many unengulfed corpses. These observations suggest that these two sets of genes are involved in distinct and partially redundant processes that act in the engulfment of cell corpses.

Animals↗
PubMed1999

Activation of caspases and p53 by bovine herpesvirus 1 infection results in programmed cell death and efficient virus release.

Programmed cell death (PCD), or apoptosis, is initiated in response to various stimuli, including virus infection. Bovine herpesvirus 1 (BHV-1) induces PCD in peripheral blood mononuclear cells at the G0/G1 phase of the cell cycle (E. Hanon, S. Hoornaert, F. Dequiedt, A. Vanderplasschen, J. Lyaku, L. Willems, and P.-P. Pastoret, Virology 232:351-358, 1997). However, penetration of virus particles is not required for PCD (E. Hanon, G. Meyer, A. Vanderplasschen, C. Dessy-Doize, E. Thiry, and P. P. Pastoret, J. Virol. 72:7638-7641, 1998). The mechanism by which BHV-1 induces PCD in peripheral blood mononuclear cells is not understood, nor is it clear whether nonlymphoid cells undergo PCD following infection. This study demonstrates that infection of bovine kidney (MDBK) cells with BHV-1 leads to PCD, as judged by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling, DNA laddering, and chromatin condensation. p53 appears to be important in this process, because p53 levels and promoter activity increased after infection. Expression of proteins that are stimulated by p53 (p21(Waf1) and Bax) is also activated after infection. Cleavage of Bcl-xL, a protein that inhibits PCD, occurred after infection, suggesting that caspases (interleukin-1beta-converting enzyme-like proteases) were activated. Other caspase substrates [poly(ADP-ribose) polymerase and actin] are also cleaved during the late stages of infection. Inhibition of caspase activity delayed cytotoxic activity and virus release but increased the overall virus yield. Taken together, these results indicate that nonlymphoid cells undergo PCD near the end of productive infection and further suggest that caspases enhance virus release.

Animals↗
PubMedDate not supplied

Hormonal regulation of programmed cell death during amphibian metamorphosis.

Extensive programmed cell death (PCD) is initiated at the onset of amphibian metamorphosis, resulting in 100% of cells dying in some larval tissues, as during total regression of tail and gills. All cell death during metamorphosis is under the control of thyroid hormone (TH), which can initiate the process precociously in whole tadpoles or in individual tissues in culture. The hormone prolactin (PRL), given exogenously, prevents natural and TH-induced metamorphosis. We have exploited this dual hormonal regulation in premetamorphic Xenopus tails in organ culture to identify and characterize early genes that are TH-induced and considered important for initiating cell death. Among the earliest genes activated by TH are those encoding the two thyroid hormone receptors TR alpha and TR beta. This autoinduction of TR genes is considered important since, in blocking this process, PRL also inhibited the expression of other TH-inducible genes and prevented cell death. The expression of early genes other than TR genes, which are known to promote cell death or survival, is also considered to be important for the initiation of PCD during amphibian metamorphosis. We are, therefore, working on the identification, characterization, and expression of members of the Xenopus bcl-2-like gene family, as well as other genes, such as nur-77 and ICE, which may act as early genes during tadpole tail regression.

Animals↗
PubMed1997

Programmed cell death during plant growth and development.

This review describes programmed cell death as it signifies the terminal differentiation of cells in anthers, xylem, the suspensor and senescing leaves and petals. Also described are cell suicide programs initiated by stress (e.g., hypoxia-induced aerenchyma formation) and those that depend on communication between neighboring cells, as observed for incompatible pollen tubes, the suspensor and synergids in some species. Although certain elements of apoptosis are detectable during some plant programmed cell death processes, the participation of autolytic and perhaps autophagic mechanisms of cell killing during aerenchyma formation, tracheary element differentiation, suspensor degeneration and senescence support the conclusion that nonapoptotic programmed cell death pathways are essential to normal plant growth and development. Heterophagic elimination of dead cells, a prominent feature of animal apoptosis, is not evident in plants. Rather autolysis and autophagy appear to govern the elimination of cells during plant cell suicide.

Journal Article↗
PubMed1996

Programmed cell death in the absence of c-Fos and c-Jun.

Programmed cell death, or apoptosis, is a normal process in the development of a variety of embryonic and adult tissues, and is also observed in several pathological conditions. Several recent studies, using both expression and functional assays, have implicated the transcription factor, AP-1, in the regulation of programmed cell death, and specifically implicate the genes c-fos and c-jun, as well as some other family members. If the products of the c-fos and/or c-jun genes are essential components in the cascade of events that leads to programmed cell death in mammalian cells, it follows that cell death would not occur in mice lacking functional copies of these genes. We have made use of null mutations in the c-fos and c-jun genes that were produced by gene targeting (Johnson, R.S., Spiegelman, B.M. and Papaioannou, V.E. (1992). Cell 71, 577-586; Johnson, R.S., Van Lingen, B., Papaioannou, V.E. and Spiegelman, B.M. (1993). Genes Dev. 7, 1309-1317) to investigate this possibility. Cell death was assayed using an in situ apoptosis assay in c-fos null embryos and adults, c-jun null embryos, and c-fos/c-jun double null embryos compared with control mice. The occurrence of cell death in c-fos null mice was also assessed in two experimental conditions that normally lead to neuronal cell death. The first was unilateral section of the sciatic nerve in neonates, which leads to the death of anterior horn cells of the spinal cord on the operated side. The second was a genetic cross combining the weaver mutation, which causes death of cerebellar granule cells, with the c-fos mutation. Our results show that programmed cell death occurs normally in developing embryonic tissues and adult thymus and ovary, regardless of the absence of a functional c-fos gene. Furthermore, absence of c-fos had no effect on neuronal cell death in the spinal cord following sciatic nerve section, or in heterozygous weavers' cerebellae. Finally, the results show that programmed cell death can take place in embryos lacking both Fos and Jun.

Animals↗
PubMed1994

Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of Cyclin D1 during programmed cell death.

Sympathetic neurons undergo RNA and protein synthesis-dependent programmed cell death when deprived of nerve growth factor. To test the hypothesis that neuronal programmed cell death is a consequence of conflicting growth signals which cause the inappropriate activation of cell cycle genes, we have analyzed cell cycle-related genes for their expression in postmitotic neurons. Surprisingly, many of these genes are expressed in neurons, although cdc2, cdk2, and cyclin A are not. During programmed cell death, the expression of most of these genes, including several cyclins and the Rb and p53 tumor suppressor genes, decreases similar to that of neuronal genes. In contrast, cyclin D1 expression is selectively induced in dying neurons. Cyclin D1 mRNA levels peak 15-20 hr after nerve growth factor withdrawal, concurrent with the time that neurons become committed to die. These results provide an extensive characterization of cell cycle gene expression in postmitotic neurons and provide the evidence for a gene induced during neuronal programmed cell death.

Animals↗
PubMed1995

Programmed cell death in the Drosophila central nervous system midline.

BACKGROUND: During the development of the central nervous system, large numbers of cells die by programmed cell death. This process requires the activity of specific gene products and subserves functions that include regulating the sizes of interacting cell populations and removing cells that provide transient functions. Resolution of programmed cell death often involves the elimination of dying cell corpses by phagocytic macrophages. In Drosophila, the reaper gene plays a crucial role in mediating programmed cell death; chromosomal deficiencies which remove reaper result in an absence of programmed cell death. We have used a reaper-deficiency mutant strain Df(3R)H99 (or H99), in conjunction with strains containing cell-type-specific markers, to examine the role of programmed cell death in differentiation of the embryonic central nervous system midline. RESULTS: Midline cell death was identified both by the presence of excess midline cells in H99 mutants and by the engulfment of dying midline cells by macrophages in wild-type embryos. These developmental deaths are lineage-specific: prominent midline glial death was observed, while little if any death was detected among the ventral unpaired median neurons. Examination of H99 mutants indicates that cell death is not required for the formation of macrophage precursors, or for their subsequent migration throughout the embryo; however, in the absence of dying cells, macrophage precursors do not exhibit morphological differentiation or phagocytosis. In both wild-type and H99 mutant embryos, a subset of macrophages migrate along the ventral midline. This midline migration is not observed in single-minded mutants, in which ventral midline cells fail to develop. CONCLUSIONS: Programmed cell death plays a crucial role in the development of the central nervous system midline, and dying midline cells are rapidly eliminated by phagocytic macrophages. It seems that the generation of engulfment signals in cells undergoing programmed cell death is downstream of reaper gene function, and that central nervous system midline and/or ventral epidermal cells provide directional cues for migrating macrophages.

Animals↗
PubMed1997

Msx2 is a transcriptional regulator in the BMP4-mediated programmed cell death pathway.

Homeobox-containing genes play an important role in patterning processes that occur during embryogenesis. Programmed cell death is a key process during pattern formation. The mechanisms by which programmed cell death is spatially regulated are not well characterized. Msx1 and Msx2 are two closely related homeobox-containing genes that are expressed at sites where cellular proliferation and programmed cell death occur, including the developing limb and the cephalic neural crest. Tissue interactions are necessary for the maintenance of Msx1 and Msx2 expression and programmed cell death. It has been demonstrated that BMP4 can regulate cell death at these same sites as well as induce Msx expression. These observations lead to the hypothesis that Msx2 is a key regulator of cell death in the BMP-mediated pathway. Embryonic stem cell lines will undergo processes typical of early embryogenesis upon aggregation and have recently been shown to provide a model system for programmed cell death. In contrast to ES cells, we see that P19 cells do not undergo pronounced cell death upon aggregation; however, constitutive ectopic Msx2 expression in P19 cells results in a marked increase in apoptosis induced upon aggregation but has no effect when cells are grown as a monolayer. If aggregates are allowed to interact with a substrate, the process of programmed cell death is completely inhibited. Addition of BMP4 to aggregated P19 cells also results in cell death; however, BMP4 does not increase levels of cell death in Msx2-expressing cells. Addition of BMP4 to P19 cells results in an induction of Msx2 transcription consistent with its proposed role in cell death in the embryo. Our data support a model by which BMP4 induces programmed cell death via an Msx2-mediated pathway and provide direct functional evidence that Msx2 expression is a regulator of this process.

Apoptosis↗
PubMed2000

Plant proteolytic enzymes: possible roles during programmed cell death.

Proteolytic enzymes are known to be associated with developmentally programmed cell death during organ senescence and tracheary element differentiation. Recent evidence also links proteinases with some types of pathogen- and stress-induced cell suicide. The precise roles of proteinases in these and other plant programmed cell death processes are not understood, however. To provide a framework for consideration of the importance of proteinases during plant cell suicide, characteristics of the best-known proteinases from plants including subtilisin-type and papain-type enzymes, phytepsins, metalloproteinases and the 26S proteasome are summarized. Examples of serine, cysteine, aspartic, metallo- and threonine proteinases linked to animal programmed cell death are cited and the potential for plant proteinases to act as mediators of signal transduction and as effectors of programmed cell death is discussed.

Apoptosis↗