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PubMed1993

Role of programmed cell death in carcinogenesis.

Cells possess within their repertoire of genetic programs the ability not only to proliferate and be functionally active, but also to activate and undergo a process of self-induced destruction. This process, called programmed cell death, involves a genetic reprogramming of the cell that results in an energy-dependent cascade of biochemical and morphological changes within the cell that result in its death and elimination. Activation of this programmed death process is controlled by a series of endogenous cell-type-specific signals. In addition, a variety of exogenous cell-damaging treatments (e.g., radiation, chemicals, and viruses) can activate this pathway if sufficient injury to the cell occurs. Because a cell must undergo a series of molecular changes to acquire the malignant phenotype and because these changes are often induced by agents or treatment that damage the cell over an extended period of time, anything that enhances the survival of initiated/damaged cells will promote the carcinogenic process. This paper presents an overview of the regulation and mechanism of programmed cell death and how derangement of this regulation may be involved in carcinogenesis.

Androgens↗
PubMed1995

Expression and activity of cell cycle regulators during proliferation and programmed cell death in the mammary gland.

In the mammary gland distinct phases of proliferation, differentiation and programmed cell death of epithelial cells occur at defined stages of development. Here we show that the expression and activity of cell cycle regulators during normal and preneoplastic proliferation and programmed cell death are remarkably similar. In all cases we found elevated levels of a protein kinase A activity and of transcription factor AP-1, cFos and JunD being the major components of the AP-1 DNA binding complex. A correlation between cFos and JunD expression and chromosomal DNA fragmentation during programmed cell death was observed. Several genes associated with G1, including cyclin D1, D2 and D3 and c-fos, c-jun, junB, JunD, c-myc and p53, are induced in proliferating and in apoptotic mouse mammary tissue. Whereas the expression of these genes correlated with active proliferation of epithelial cells in terminal end buds during puberty, very little proliferation or DNA synthesis, but, instead, extensive apoptosis of epithelial cells, was observed during involution. Our results suggest that a G1-like state is associated with programmed cell death of mammary epithelial cells in vivo and that apoptosis occurs without S-phase induction.

Journal Article↗
PubMed1994

The ins and outs of programmed cell death during C. elegans development.

During the development of the C. elegans hermaphrodite, 131 of the 1090 cells generated undergo programmed cell death. Genetic studies have identified mutations in 14 genes that specifically affect this process. These genes define a genetic pathway for programmed cell death in C. elegans. Two genes, ced-3 and ced-4, are required for cells to undergo programmed cell death, while a third gene, ced-9, protects cells that should live from undergoing programmed cell death. The proteins encoded by ced-3 and ced-9 show significant similarity to proteins that affect programmed cell death in vertebrates, suggesting that the molecular cell death pathway in which ced-3, ced-4, and ced-9 act has been conserved between nematodes and vertebrates.

Animals↗
PubMed2003

Genome-wide analyses of steroid- and radiation-triggered programmed cell death in Drosophila.

Apoptosis and autophagy are two forms of programmed cell death that play important roles in the removal of unneeded and abnormal cells during animal development. While these two forms of programmed cell death are morphologically distinct, recent studies indicate that apoptotic and autophagic cell death utilize some common regulatory mechanisms. To identify genes that are associated with apoptotic and autophagic cell death, we monitored changes in gene transcription by using microarrays representing nearly the entire Drosophila genome. Analyses of steroid-triggered autophagic cell death identified 932 gene transcripts that changed 5-fold or greater in RNA level. In contrast, radiation-activated apoptosis resulted in 34 gene transcripts that exhibited a similar magnitude of change. Analyses of these data enabled us to identify genes that are common and unique to steroid- and radiation-induced cell death. Mutants that prevent autophagic cell death exhibit altered levels of gene transcription, including genes encoding caspases, non-caspase proteases, and proteins that are similar to yeast autophagy proteins. This study also identifies numerous novel genes as candidate cell death regulators and suggests new links between apoptosis and autophagic cell death.

Animals↗
PubMed1989

Retinoic-acid-induced limb-reduction defects: perturbation of zones of programmed cell death as a pathogenetic mechanism.

Pregnant C57Bl/6J mice were treated with 100 mg/kg body weight of all-trans retinoic acid in sesame oil on day 11.0 of gestation. Among the live fetuses harvested on day 18 of gestation, 100% had mesomelic defects of the limbs as determined by gross examination and skeletal staining. Control fetuses treated with sesame oil had no observable limb malformations. Some treated and control embryos were harvested 12 hr after treatment and examined for patterns of cell death by using the supravital stain Nile blue sulphate and methylene-blue- and acid-fuchsin-stained histological sections. Retinoic-acid-induced cell death in the core of the limb was always associated with the zones of programmed cell death as seen in control embryos of comparable stages. This, in concert with previous studies demonstrating excessive cell death in regions of programmed cell death that correlated with subsequent malformations, leads us to conclude that the pathogenesis of mesomelic malformations has a primary association with the phenomenon of programmed cell death.

Abnormalities, Drug-Induced↗
PubMed1994

Programmed cell death in response to alkyllysophospholipids in endothelial cells.

Addition of the alkyllysophospholipid ET16-OMe, a putative antitumor drug, to the culture medium of human vascular endothelial cells resulted in apoptotic cell death. The death was characterized as programmed cell death since the process was inhibited by the addition of an inhibitor of protein synthesis. The mechanism responsible for apoptosis induced by alkyllysophospholipid has unique characteristics, as compared to those of apoptosis induced by other antitumor drugs, since the drug caused fragmentation of dying cells and its effect could be overcome by the presence of a survival factor, namely, fibroblast growth factor.

Antineoplastic Agents↗
PubMed1993

Delayed internucleosomal DNA fragmentation in programmed cell death.

DNA fragmentation was evaluated in three instances of programmed cell death, interdigital cell death in embryonic mouse limbs, and metamorphic death of both the labial glands and intersegmental muscle in the tobacco hornworm Manduca sexta. In the mouse, we evaluated both developmental cell death and expanded-range cell death induced by retinoic acid. The status of DNA was examined in several ways. Nuclei were examined by electron microscopy and Feulgen staining. Quantitative assessment of total DNA content in Feulgen-stained degenerating nuclei was made for the gland. In the labial gland, DNA content does not drop during the early phases of cell death; nor is an endonucleolytic ladder seen when DNA was examined by ethidium bromide staining or prelabeling with [3H]thymidine. Only by using end labeling of DNA could we detect DNA fragmentation at a very late stage in cell death, day 4 of the collapse of the gland. In contrast, WEHI 7.1 lymphoma cells display an early and extensive ladder after treatment with glucocorticoids. In mouse limb, for which cell death follows a more classic apoptotic morphology, a ladder is likewise not seen. We conclude that activation of an endonuclease is neither a trigger nor a necessary or defining component of the early phases of developmental programmed cell death, and that reported failure by others to find such a ladder may depend on limitations in the system that is under investigation.

Animals↗
PubMed1995

Tyrphostin induces non-apoptotic programmed cell death in colon tumor cells.

The programmed cell death inducing effect of the EGF receptor tyrosine kinase inhibitor alpha-cyano-3,4-dihydroxycinnamthioamide (AG213) was investigated in vitro on HT-29 human colon tumor. AG213 at concentrations between 45 to 450 microM blocks the proliferation of HT-29 cells. Morphological findings suggest that the selective tyrosine kinase inhibitor AG213 induces Clarke III type (non-lysosomal vesiculate cytoplasmic) programmed cell death; unlike ATP analog non-selective tyrosine kinase inhibitors like Genistein which were found to induce apoptosis. Cycloheximide and Actinomycin-D reduced the effect of AG213 pointing to the fact that protein and RNA synthesis are also needed for this form of cell death. Acid phosphatase activity was found in the Golgi and in the newly formed intracytoplasmic vacuoles 3 hours after AG213 treatment which disappeared by 6 hours. The induction of Clarke III cell death by tyrosine kinase inhibitors may open a new modality to selective killing of tumor cells.

Acid Phosphatase↗
PubMed2001

Does the redox status of cytochrome C act as a fail-safe mechanism in the regulation of programmed cell death?

It has now become recognized that one of the key events in the induction of apoptosis, or programmed cell death, in both plants and animals is the release of cytochrome c from mitochondria. It is also known that oxidative stress imposed on cells can have a profound effect on the onset or progression of apoptosis. Here, we discuss how the redox status of cytochrome c, and thus its structure, can be altered by the presence of reactive oxygen species (ROS) and reduced glutathione (GSH). We suggest that cytochrome c will only induce programmed cell death if present in the cytoplasm in the oxidized state, and that the presence of high levels of cytoplasmic GSH maintain cytochrome c in an inactive (reduced) state, thus behaving as a fail-safe mechanism if cytochrome c is released by mitochondria when programmed cell death is not the required outcome. If the redox status of the cell is disturbed however, perhaps in the presence of hydrogen peroxide, GSH concentrations will drop, the cellular E(h) will rise, and cytochrome c will tend towards the oxidized state, allowing programmed cell death to proceed. Therefore, we propose that the redox state of cytoplasmic cytochrome c may be a key regulator of programmed cell death.

Animals↗
PubMed2004

Caspase-dependent inactivation of proteasome function during programmed cell death in Drosophila and man.

The caspase family of cysteine proteases plays a conserved role in the coordinate demolition of cellular structures during programmed cell death from nematodes to man. Because cells undergoing programmed cell death in nematodes, flies, and mammals all share common features, this suggests that caspases target a common set of cellular structures in each of these organisms. However, although many substrates for mammalian caspases have been identified, few substrates for these proteases have been identified in invertebrates. To search for similarities between the repertoires of proteins targeted for proteolysis by caspases in flies and mammals, we have performed proteomics-based screens in Drosophila and human cell lines undergoing apoptosis. Here we show that several subunits of the proteasome undergo caspase-dependent proteolysis in both organisms and that this results in diminished activity of this multicatalytic protease complex. These data suggest that caspase-dependent proteolysis decreases protein turnover by the proteasome and that this is a conserved event in programmed cell death from Drosophila to mammals.

Animals↗
PubMed2002

DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death.

Death-associated protein kinase (DAPk) and DAPk-related protein kinase (DRP)-1 proteins are Ca+2/calmodulin-regulated Ser/Thr death kinases whose precise roles in programmed cell death are still mostly unknown. In this study, we dissected the subcellular events in which these kinases are involved during cell death. Expression of each of these DAPk subfamily members in their activated forms triggered two major cytoplasmic events: membrane blebbing, characteristic of several types of cell death, and extensive autophagy, which is typical of autophagic (type II) programmed cell death. These two different cellular outcomes were totally independent of caspase activity. It was also found that dominant negative mutants of DAPk or DRP-1 reduced membrane blebbing during the p55/tumor necrosis factor receptor 1-induced type I apoptosis but did not prevent nuclear fragmentation. In addition, expression of the dominant negative mutant of DRP-1 or of DAPk antisense mRNA reduced autophagy induced by antiestrogens, amino acid starvation, or administration of interferon-gamma. Thus, both endogenous DAPk and DRP-1 possess rate-limiting functions in these two distinct cytoplasmic events. Finally, immunogold staining showed that DRP-1 is localized inside the autophagic vesicles, suggesting a direct involvement of this kinase in the process of autophagy.

Antigens, CD↗
PubMed1994

Genetic control of programmed cell death in Drosophila.

A gene, reaper (rpr), that appears to play a central control function for the initiation of programmed cell death (apoptosis) in Drosophila was identified. Virtually all programmed cell death that normally occurs during Drosophila embryogenesis was blocked in embryos homozygous for a small deletion that includes the reaper gene. Mutant embryos contained many extra cells and failed to hatch, but many other aspects of development appeared quite normal. Deletions that include reaper also protected embryos from apoptosis caused by x-irradiation and developmental defects. However, high doses of x-rays induced some apoptosis in mutant embryos, and the resulting corpses were phagocytosed by macrophages. These data suggest that the basic cell death program is intact although it was not activated in mutant embryos. The DNA encompassed by the deletion was cloned and the reaper gene was identified on the basis of the ability of cloned DNA to restore apoptosis to cell death defective embryos in germ line transformation experiments. The reaper gene appears to encode a small peptide that shows no homology to known proteins, and reaper messenger RNA is expressed in cells destined to undergo apoptosis.

Amino Acid Sequence↗
PubMed2004

Programmed cell death in the development of the vertebrate inner ear.

Programmed cell death is known to be an essential process for accurate ontogeny during the normal development of the inner ear. The inner ear is a complex sensory organ responsible for equilibrium and sound detection in vertebrates. In all vertebrates, the inner ear develops from a single ectodermic patch on the surface of the embryo's head, which undergoes a series of morphological changes to give rise to the complex structure of the adult inner ear. Enlargement and morphogenesis of the inner ear primordium is likely to depend on cellular division, growth, migration, differentiation and apoptosis. Here we describe the regions of programmed cell death that contribute to the final morphological aspect of the adult inner ear. The few studies that focus on the molecules that control this process during inner ear development indicate that the molecules and intracellular signaling pathways activated during the apoptotic response in the inner ear are similar to the previously described for the nervous system. In this review, we will describe some of the growth factors and key pathways that regulate pro- and anti-apoptotic signals and how they cross talk to determine the apoptotic or survival fate of cells in the development of the inner ear.

Animals↗
PubMed1996

Specific toxicity of tunicamycin in induction of programmed cell death of sympathetic neurons.

Tunicamycin belongs to a group of antibiotics which can cause severe a nd often fatal neurological malfunction in animals, commonly known as "annual ryegrass toxicity." At the cellular level, tunicamycin is a potent glycosylation inhibitor which is often used to elucidate the importance of glycosylation in protein functions. Earlier reports suggested that tunicamycin was able to interfere with the binding of nerve growth factor to its receptors. In this report, we showed that tunicamycin was able to kill sympathetic neurons in cultures. The mechanism of cell death was observed to be similar to that of "programmed cell death" in sympathetic neurons induced by nerve growth factor deprivation. Such tunicamycin-induced cell death could be prevented by the protein synthesis inhibitor cycloheximide, which was known to prevent the programmed cell death in sympathetic neurons. These results demonstrated that, in addition to the proven CNS neurotoxicity in animals, tunicamycin causes programmed cell death in peripheral (sympathetic) neurons.

Animals↗
PubMed2001

Steroid regulation of autophagic programmed cell death during development.

Apoptosis and autophagy are morphologically distinct forms of programmed cell death. While autophagy occurs during the development of diverse organisms and has been implicated in tumorigenesis, little is known about the molecular mechanisms that regulate this type of cell death. Here we show that steroid-activated programmed cell death of Drosophila salivary glands occurs by autophagy. Expression of p35 prevents DNA fragmentation and partially inhibits changes in the cytosol and plasma membranes of dying salivary glands, suggesting that caspases are involved in autophagy. The steroid-regulated BR-C, E74A and E93 genes are required for salivary gland cell death. BR-C and E74A mutant salivary glands exhibit vacuole and plasma membrane breakdown, but E93 mutant salivary glands fail to exhibit these changes, indicating that E93 regulates early autophagic events. Expression of E93 in embryos is sufficient to induce cell death with many characteristics of apoptosis, but requires the H99 genetic interval that contains the rpr, hid and grim proapoptotic genes to induce nuclear changes diagnostic of apoptosis. In contrast, E93 expression is sufficient to induce the removal of cells by phagocytes in the absence of the H99 genes. These studies indicate that apoptosis and autophagy utilize some common regulatory mechanisms.

Animals↗
PubMed1998

EGF-induced programmed cell death of human mammary carcinoma MDA-MB-468 cells is preceded by activation AP-1.

MDA-MB-468 is a human mammary adenocarcinoma cell line that overexpresses the epidermal growth factor (EGF) receptor and undergoes programmed cell death (apoptosis) in response to EGF treatment. Programmed cell death was shown to be greatly enhanced when cells were growth-arrested prior to EGF treatment. Apoptosis was characterized by an initial rounding up and detachment of the cells from their substrate starting about 12 h after EGF treatment, followed by chromatin condensation, nuclear fragmentation and oligonucleosomal fragmentation of the DNA at about 24 to 48 h. Cell death was dependent on de novo protein synthesis. We found a rapid induction of c-fos, c-jun and junB at the mRNA level after about 30 min of EGF treatment and a more delayed upregulation of fosB and fra-1. The junD gene was expressed in the absence of EGF, and it was moderately induced within 30 min of growth factor addition. The increase of the different fos and jun mRNAs were paralleled by an increase of activator protein-1 (AP-1) DNA binding activity. A characterization of the AP-1 complex revealed similar levels of several Fos and Jun proteins. Based on the kinetics of AP-1 accumulation and cell death, it seems likely that AP-1 contributes to the apoptotic cell death of EGF receptor-overexpressing MDA-MB-486 cells.

Apoptosis↗
PubMed2002

Programmed cell death and its clinical implications.

Cell death is a highly regulated process that is ubiquitous in all eukaryotes. Programmed cell death (PCD) is an integral part of both animal and plant development. Studies on apoptosis, the well characterized form of programmed cell death led to the identification of a central tripartite death switch i.e. apoptosome consisting of Apaf-1, Apaf-2 and Apaf-3. The caspases, a family of cysteine-dependent aspartate directed-proteases, constitute the central executioners of apoptosis. Much of the attention on programmed cell death is focused on caspases, however, cell death can still occur even when the caspase cascade is blocked, revealing the existence of nonapoptotic alternative pathway(s) of cell death. The mitochondrial release of cytochrome C following a PCD inducing stimulus in both plants and animals suggests the evolutionary conservation of death pathways. Dysregulation of apoptosis may be related to the development of several disease states as well as ageing. Excessive apoptosis is associated with neurodegenerative disorders, AIDS etc., whereas deficient apoptosis is associated with cancer, auto-immunity, viral infections etc. Understanding the regulation of programmed cell death would throw light in designing drugs and gene therapies that can target specific molecules in the apoptotic pathway opening the vistas for new therapeutic endeavors in many areas of medicine.

Apoptosis↗
PubMed2000

An essential role for the caspase dronc in developmentally programmed cell death in Drosophila.

Dronc is a caspase recruitment domain-containing Drosophila caspase that is expressed in a temporally and spatially restricted fashion during development. Dronc is the only fly caspase known to be regulated by the hormone ecdysone. Here we show that ectopic expression of dronc in the developing fly eye leads to increased cell death and an ablated eye phenotype that can be suppressed by halving the dosage of the genes in the H99 complex (reaper, hid, and grim) and enhanced by mutations in diap1. In contrast to previous reports, we show that the dronc eye ablation phenotype can be suppressed by coexpression of the baculoviral caspase inhibitor p35. Dronc also interacts, both genetically and biochemically, with the CED-4/Apaf-1 fly homolog, Dark. Furthermore, extracts made from Dark homozygous mutant flies have reduced ability to process Dronc, showing that Dark is required for Dronc processing. Finally, using the RNA interference technique, we show that loss of Dronc function in early Drosophila embryos results in a dramatic decrease in cell death, indicating that Dronc is important for programmed cell death during embryogenesis. These results suggest that Dronc is a key caspase mediating programmed cell death in Drosophila.

Animals↗