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At least 19 recordsLinked to original sources
PubMed1992

Insect muscle as a model for programmed cell death.

Programmed cell death (PCD) is a fundamental component of development in virtually all animals. Despite the ubiquity of this phenomenon, little is known about what tells a cell to die, and less still about the physiological and molecular mechanisms that bring about death. One system that has proven to be very amenable for the study of PCD is the intersegmental muscle (ISM) of the tobacco hawkmoth Manduca sexta. These giant muscle cells are used during the eclosion (emergence) behavior of the adult moth, and then die during the subsequent 30 h. This review uses the ISMs as a model system to address questions that are basic to any cell death system, including the following: (1) how do cells know when to die; (2) what physiological changes accompany death; (3) what are the molecular mechanisms that mediate death; and (4) do all cells die by the same process? For the ISMs, the trigger for PCD is a decline in the circulating titer of the insect molting hormone, 20-hydroxyecdysone (20-HE). During cell death there are rapid decreases in both the myofibrillar sensitivity to intracellular calcium and the resulting force of fiber contraction. The ability of the ISMs to undergo PCD requires the repression and activation of specific genes. Two of the repressed genes encode actin and myosin. One of the upregulated presumptive cell-death genes encodes polyubiquitin, which appears to play a critical role in the rapid proteolysis that accompanies ISM death.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Social controls on cell survival and cell death.

Programmed cell death occurs in most animal tissues at some stage of their development, but the molecular mechanism by which it is executed is unknown. For some mammalian cells, programmed death seems to occur by default unless suppressed by signals from other cells. Such dependence on specific survival signals provides a simple way to eliminate misplaced cells, for regulating cell numbers and, perhaps, for selecting the fittest cells. But how general is this dependence on survival signals?

Animals↗
PubMed1992

Negative regulators of programed cell death.

During animal development many cells undergo programed deaths. Recently, genes that suppress the cell-death program have been described in both vertebrates and invertebrates. These genes play a vital role in regulation of the molecules that kill cells, and disruption of this regulatory process can contribute to disease.

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↗
PubMed1992

Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.

The classical type of programmed cell death is characterized by its dependence on de novo RNA and protein synthesis and morphological features of apoptosis. We confirmed that stimulated 2B4.11 (a murine T-cell hybridoma) and interleukin-3 (IL-3)-deprived LyD9 (a murine haematopoietic progenitor cell line) died by the classical type of programmed cell death. Assuming that common biochemical pathways might be involved in the deaths of 2B4.11 and LyD9, we isolated the PD-1 gene, a novel member of the immunoglobulin gene superfamily, by using subtractive hybridization technique. The predicted PD-1 protein has a variant form of the consensus sequence found in cytoplasmic tails of signal transducing polypeptides associated with immune recognition receptors. The PD-1 gene was activated in both stimulated 2B4.11 and IL-3-deprived LyD9 cells, but not in other death-induced cell lines that did not show the characteristic features of the classical programmed cell death. Expression of the PD-1 mRNA in mouse was restricted to the thymus and increased when thymocyte death was augmented by in vivo injection of anti-CD3 antibody. These results suggest that activation of the PD-1 gene may be involved in the classical type of programmed cell death.

Amino Acid Sequence↗
PubMed1991

Identification of mRNAs associated with programmed cell death in immature thymocytes.

Programmed cell death is an essential cellular process that occurs in epithelial turnover, neural development, and regulation of cell populations of the immune system. Thymocytes undergo programmed cell death in response to several inductive stimuli, including exposure to glucocorticoids or radiation. This program can be blocked by inhibitors of RNA or protein synthesis; this implies that new proteins are required to execute the death programs. To search for possible death-associated mRNAs, we directionally cloned cDNA representing mRNA from control and dexamethasone-treated thymocytes. These libraries were used to produce ample amounts of DNA and RNA used in subtractive hybridization for the removal of sequences present in both control and induced cells. The remaining unhybridized sequences were selectively amplified by polymerase chain reaction and cloned to produce a library enriched for sequences expressed in death-induced cells. From this library we isolated cDNAs of death-associated mRNAs. One of these mRNAs, RP-8, appears within 1 h after exposure to gamma radiation, and a second mRNA, RP-2, is observed within 2 h. Both of these mRNAs accumulate during a period when a reference mRNA, actin, is declining. RP-2 and RP-8 are no longer detectable after 6 h postinduction, when apoptosis and mRNA degradation are evident in the culture. Sequence analysis of RP-8 cDNA indicates the presence of a zinc finger domain suggestive of a possible DNA regulatory role for the RP-8 protein. cDNA sequence results on RP-2 classify the corresponding protein as an integral membrane protein. We conclude that RP-2 and RP-8 are death-associated mRNAs that should be functionally evaluated in the context of the death process. As previously suggested, it may be that a family of "death genes" is activated by various stimuli depending on the type of cell, in a manner somewhat analogous to the induction of heat shock (stress) protein genes.

Amino Acid Sequence↗
PubMed1991

Programmed cell death (apoptosis): its virological and immunological connections (a review).

Programmed cell death is a physiological, energy-consuming mechanism leading to suicide of the cell. Cell death is accomplished by the activation of endonucleases that fragment the cell's nuclear DNA. Some tumour cells remain susceptible to programmed death. These are hormone- and growth factor-dependent tumour cells. Hormone or growth factor deprivation induces signals leading to apoptosis. Other tumours gain strong resistance to apoptosis. One of the normal functions of the bcl-2 gene is to provide longevity to memory B cells. When this gene becomes translocated in follicular B cell lymphomas, it renders lymphoma cells resistant to apoptosis. Latent membrane protein encoded by an EBV gene, either by itself or by amplifying bcl-2, enables tumour cells (nasopharyngeal carcinoma; Reed-Sternberg cell of Hodgkin's disease) to resist apoptotic death. Loss of antioncogene p53 provides for resistance against programmed cell death. Breakdown of resistance to apoptosis in tumour cells can be achieved by oncolytic viruses; generation of lymphotoxin and tumour necrosis factor; monoclonal antibodies; transfection with plasmid vectors carrying p53; gamma irradiation; and certain chemotherapeutic agents.

Autoantibodies↗
PubMed1992

Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2.

Programmed cell death is a physiological process that eliminates unwanted cells. The bcl-2 gene regulates programmed cell death in mammalian cells, but the way it functions is not known. Expression of the human bcl-2 gene in the nematode Caenorhabditis elegans reduced the number of programmed cell deaths, suggesting that the mechanism of programmed cell death controlled by bcl-2 in humans is the same as that in nematodes.

Animals↗
PubMed1992

Programmed cell death: concept, mechanism and control.

Programmed cell death or apoptosis occurs under physiological conditions as a result of physiological effectors. It is a relatively slower process and requires active participation of the cell in the suicidal mechanism. Apoptosis is controlled by precise intrinsic genetic programme and may be induced by almost all those stimuli causing necrosis. The role played by the intensity in determining the death process and the underlying mechanism is imperfectly understood. Morphologically apoptotic cells appear as small condensed body. The chromatin is dense and fragmented, packed into compact membrane-bound bodies together with randomly distributed cell organelles. The plasma membrane loses its characteristic architecture and shows extensive blebbing. It buds off projections so that the whole cell may split into several membrane-bound apoptotic bodies. Significant chemical changes take place in the plasma membrane. This helps in recognition of the apoptotic bodies by phagocytes. At this moment it is unclear if all cells can undergo apoptosis or it is a characteristic of only some tissues which are predisposed to apoptotic death being directly under the control of hormones or growth factors. Experimental studies aimed at comparison of induction of apoptosis in cells of different origin are warranted to elucidate this point. Biochemically a pre-commitment step for induction of death programmation through macromolecular synthesis is essential for most systems. The double-stranded linker DNA between nucleosomes is cleaved at regular inter-nucleosomal sites through the action of a Ca2+, Mg(2+)-sensitive neutral endonuclease. Zinc is a potent inhibitor of the enzyme. Calcium probably plays a key controlling role in activation of the enzyme since prevention of Ca2+ increase prevents endonuclease activation. It is becoming evident that signal transduction through appropriate receptors control the Ca2+ flux in the cells. Most apoptotic cells require synthesis of RNA and proteins. Delay or abrogation of apoptosis by inhibition of macromolecular synthesis is well known. The dying cells show high mRNA levels for several enzymes. Several degradative enzymes become active. Regulatory proteins maintain control over the apoptotic cascade. At the molecular level, search has been initiated for the mammalian equivalents of the cell death (ced) gene. Activation of several specific genes is indicated. Specific expression of cell death-associated gene products (e.g. TRPM-2/SGP-2) has been reported in several unrelated apoptotic cell systems. Sequential induction of c-fos, c-myc and 70 kDa heat shock protein is reported. Studies demonstrate that certain genes must remain in a transcriptionally active demethylated state during programmed cell death. Recent evidences clearly indicate that apoptosis may be positively or negatively modulated by certain genes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Anti-IgM antibody-induced cell death in a human B lymphoma cell line, B104, represents a novel programmed cell death.

We investigated the mechanisms of anti-IgM antibody-induced cell death in a recently established human surface IgM+ IgD+ B lymphoma cell line, B104, the growth of which is irreversibly inhibited by anti-IgM antibody but not by anti-IgD antibody, and compared it with the cell death of T cells via TCR/CD3 complex and with the cell death of a murine anti-IgM antibody-sensitive B lymphoma cell line, WEHI-231. The rapid time course of B104 cell death and its requirements for de novo macromolecular synthesis and Ca2+ influx suggest that anti-IgM antibody-induced B104 cell death is an active Ca(2+)-dependent programmed cell death. Moreover, cyclosporin A rescued B104 cells from this lethal signal, via surface IgM, suggesting that the intracellular mechanisms involved are quite similar to those of T cell death. DNA fragmentation, which has been reported in TCR/CD3 complex-mediated T cell death, apoptosis, was not involved in the B104 cell death process, but the possible involvement of DNA single-strand breaks was suggested. Observations under light microscopy and transmission electron microscopy indicated that the morphologic features of dying B104 cells resembled necrosis rather than apoptosis. B104 cell death was shown to be quite distinct from that of WEHI-231 in cell death kinetics, the mode of cell death, and the response to cyclosporin A. These data collectively indicate that the death of B104 cells resulting from surface IgM cross-linking represents a hitherto undefined mode of programmed cell death.

Antibodies, Anti-Idiotypic↗
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↗
PubMed1991

Programmed cell death (apoptosis) is induced rapidly and with positive cooperativity by activation of cyclic adenosine monophosphate-kinase I in a myeloid leukemia cell line.

Programmed death (apoptosis) of the rat myelocytic leukemic cell line IPC-81 was triggered by cyclic adenosine monophosphate (cAMP) analogs or by agents (cholera toxin, prostaglandins) increasing the endogenous cAMP level. The induction of cell death by cholera toxin was preceded by increased activation of cAMP-kinase. Cell lysis started already 5 hr after cAMP challenge and was preceded by internucleosomal DNA fragmentation and morphological changes characteristic of apoptosis. The cell suicide could be prevented by inhibitors of macromolecular synthesis. cAMP analogs induced cell death in a positively cooperative manner (apparent Hill coefficient of 2.9), indicating that triggering of the apoptotic process was under stringent control. There was a strong synergism between cAMP analogs complementing each other in the activation of cAMP-dependent protein kinase I (cAKI). No such synergism was noted for analogs complementing each other in the activation of cAKII. It is concluded that apoptosis can be induced solely by activation of cAKI. The IPC-81 cells expressed about four times more cAKI than cAKII. The expression of cAK subunits, on the protein and mRNA levels, was only minimally affected by cholera toxin treatment.

Animals↗
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↗
PubMed1992

[Apoptosis or programmed cell death: concepts, mechanisms and contribution in oncology].

Programmed cell death, or apoptosis, corresponds to a sequence of intracellular events that lead to cell death. It has been shown that apoptosis is necessary in some physiological conditions such as embryogenesis, homeostasis of the immune system, erythropoiesis, etc. Some xenobiotics can induce apoptosis at lower doses and necrosis at higher doses. When a cell dies, it is either by apoptosis or by necrosis, and there are many differences between these two deaths. Apoptosis begins by a pre-commitment phase, which is reversible; during this phase the cell has a high level of second messengers. The commitment phase then follows and is irreversible, even when the xenobiotic that triggered the induction is removed. Most often, apoptotic cell death requires synthesis of macromolecules, the inhibition of their synthesis can prevent it. The cell undergoes important morphological changes during apoptosis, its volume decreases when its density increases. Then chromatin becomes granular, intensively osmiophilic, it condenses along the nuclear membrane. Later, chromatin disintegrates into small granules which will be phagocytized. One of the most important characteristics of the programmed cell death is the activation of an endonuclease, that gives rise to DNA fragments of 180-200 base pairs or multiples of these numbers; then after electrophoresis, the DNA gives the appearance of a ladder. Apoptotic cells can be characterized after classic staining, and flow cytometry; they can be separated from other cells by centrifugation on a gradient of density. It has been hypothesized that cell transformation could be due to a sudden resistance to apoptosis. However, the most interesting aspect in oncology recently demonstrated is that well-known anticancer drugs are able to induce apoptosis. One can hope that the discovery of new targets for anticancer drugs could lead to discovering new drugs that could be more active.

Animals↗
PubMed1990

Evidence linking programmed cell death in the blastocyst to polyamine oxidation.

Programmed cell death occurs in the inner cell mass during blastulation concomitant with the loss of its trophectodermal potential, and blastocele fluid kills malignant inner cell mass cells with trophectodermal potential (ECa 247) but spares those with embryonic potential (P19). A previous study had shown that blastocele-like fluid from embryoid bodies of the teratocarcinoma C44 contains a low-molecular-weight cytotoxin that exhibits the same target-cell selectivity as normal blastocele fluid. The current paper shows that the preferential killing of cells with trophectodermal potential is caused by hydrogen peroxide generated during the oxidation of polyamines in the cyst fluid by amine oxidases. The greater resistance of cells with embryonic potential to hydrogen peroxide is due to glutathione-dependent mechanisms. These data lead to the conclusion that an amine oxidase in the blastocyst oxidizes polyamines in blastocele fluid, generating hydrogen peroxide which causes programmed cell death of normal and malignant cells with trophectodermal potential.

Animals↗
PubMedDate not supplied

Programmed cell death (apoptosis) in murine blastocysts: extracellular free-radicals, polyamines, and other cytotoxic agents.

Programmed cell death can also be caused by extracellular, soluble factors, some of which are not physiologic. In vivo in the murine blastocyst, apoptosis eliminates redundant cells of unneeded phenotypes (pre-trophectoderm) from the inner cell mass. Although only a few cells die and many survive, all of the cells are exposed to the extracellular H2O2 in blastocele fluid. The specific control of life versus death is due to the developmental expression of glutathione-dependent protective mechanisms in the surviving cells. Based on recent results, a model is proposed in which apoptosis and necrosis reflect different temporal points along a single cell death program.

Animals↗
PubMed1989

Biochemical evidence for programmed cell death in rabbit uterine epithelium.

Uterine epithelial cell proliferation, differentiation, and death are known to be regulated by estrogen and progesterone. The authors investigated a specific pattern of cell death called apoptosis, or programmed cell death, which is biochemically characterized by a specific pattern of DNA degradation. DNA isolated from endometrium of ovariectomized pseudopregnant rabbits showed a pattern of DNA cleavage at internucleosomal locations. In comparison, DNA from the endometrium of non-ovariectomized animals, as well as several other organs, did not exhibit that pattern. This biochemical evidence supports previous and present morphologic data and correlates with it. Under the experimental conditions used, only the uterine epithelial compartment of the endometrium shows apoptotic cell death, which is absent in the stromal compartment.

Animals↗
PubMed1992

The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death.

Mutations in the gene ced-4 block almost all of the programmed cell deaths that normally occur during Caenorhabditis elegans development. We have cloned the ced-4 gene using a ced-4 mutation caused by the insertion of the transposon Tc4. When microinjected into a ced-4 animal, a 4.4 kb DNA fragment derived from the wild-type strain and corresponding to the region of the Tc4 insertion in the mutant ced-4(n1416) rescues the Ced-4 mutant phenotype. The ced-4 gene encodes a 2.2 kb RNA transcript. This mRNA is expressed primarily during embryogenesis, when most programmed cell deaths occur. The Ced-4 protein, as deduced from cDNA and genomic DNA clones, is 549 amino acids in length. Two regions of the putative Ced-4 protein product show some similarity to known calcium-binding domains.

Amino Acid Sequence↗