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PubMed1997

Is programmed cell death required for neural tube closure?

Programmed cell death (PCD) plays an important part in animal development. It is responsible for eliminating the cells between developing digits, for example, and is involved in hollowing out solid structures to create cavities (reviewed in [1] [2]). There are many cases, however, where PCD occurs in developing tissues but its function is unknown. Important examples are seen during the folding, pinching off, and fusion of epithelial sheets during vertebrate morphogenesis, as in the formation of the neural tube and lens vesicle [2]; PCD is an invariable accompaniment to these processes, but it is unclear whether it is required for the processes to occur or is just an unavoidable consequence of them. There is increasing evidence that PCD in animals is mediated by a family of cysteine proteases, known as caspases, which are thought to act in a proteolytic cascade, cleaving one another and key intracellular proteins to kill the cell in a controlled way [3] [4]. Inhibitors of caspases are, therefore, potential tools for studying the roles of PCD during animal development [5] [6]. Here, we show that peptide caspase inhibitors block neural tube closure in explanted chick embryos, suggesting that PCD is required for this crucial developmental process.

Animals↗
PubMed2000

Programmed cell death in the developing human telencephalon.

Programmed cell death (PCD) in the form of apoptosis is recognized as one of the central events in the development of the central nervous system. To study the time of onset, extent and distribution of PCD in the human telencephalon, embryos and fetuses from 4.5 to 27 gestational weeks (g.w.) were examined using the TUNEL (TdT-mediated dUTP-biotin nick-end labelling) in situ method. At 4.5 g.w. sparse TUNEL(+) nuclei were observed in the ventricular zone of the neural tube. With the formation of the cortical plate at 7-8 g.w. , TUNEL(+) nuclei were seen in all developmental layers of the cortical anlage, as well as in the subcortical regions such as the ganglionic eminence and the internal capsule. The proliferative zones (the ventricular zone, the subventricular zone and the ganglionic eminence) contained the majority of all apoptotic nuclei observed in each specimen. However, the apoptotic index was highest in the subplate zone and in layer I. Double-labelling experiments suggested that neuronal precursors were the main population of cells undergoing PCD in the first trimester of gestation, whereas glial cells probably start dying around midgestation. The onset of labelling of microglial cells and apoptotic nuclei were synchronous, indicating the involvement of microglia in PCD. In conclusion, two distinct types of PCD were observed during human telencephalic development: embryonic apoptosis, which was synchronous with proliferation and migration of neuronal cells and probably not related to establishment of neuronal circuitry, and fetal apoptosis, which coincided with differentiation and synaptogenesis, and therefore may be related to the development of axonal-target connectivity.

Apoptosis↗
PubMed2001

An orchestrated gene expression component of neuronal programmed cell death revealed by cDNA array analysis.

Programmed cell death (PCD) during neuronal development and disease has been shown to require de novo RNA synthesis. However, the time course and regulation of target genes is poorly understood. By using a brain-biased array of over 7,500 cDNAs, we profiled this gene expression component of PCD in cerebellar granule neurons challenged separately by potassium withdrawal, combined potassium and serum withdrawal, and kainic acid administration. We found that hundreds of genes were significantly regulated in discreet waves including known genes whose protein products are involved in PCD. A restricted set of genes was regulated by all models, providing evidence that signals inducing PCD can regulate large assemblages of genes (of which a restricted subset may be shared in multiple pathways).

Algorithms↗
PubMed2006

Adaptive roles of programmed cell death during nervous system development.

The programmed cell death (PCD) of developing cells is considered an essential adaptive process that evolved to serve diverse roles. We review the putative adaptive functions of PCD in the animal kingdom with a major focus on PCD in the developing nervous system. Considerable evidence is consistent with the role of PCD in events ranging from neurulation and synaptogenesis to the elimination of adult-generated CNS cells. The remarkable recent progress in our understanding of the genetic regulation of PCD has made it possible to perturb (inhibit) PCD and determine the possible repercussions for nervous system development and function. Although still in their infancy, these studies have so far revealed few striking behavioral or functional phenotypes.

Adaptation, Physiological↗
PubMed1994

[Apoptosis--programmed cell death].

Apoptosis is a structurally distinct programmed cell death pathway. It takes place during embryogenesis, after withdrawal of the trophic hormones and in the course of normal tissue turnover. Defective regulation of apoptosis may play a very important role in the aetiology of cancer and other diseases. In this paper these and other problems concerning with apoptosis are reviewed.

Animals↗
PubMed2004

Role of programmed cell death in normal neuronal development and function.

The consequences of eliminating the process of programmed cell death during the development of the nervous system is examined by reviewing studies in the genetic model organisms Caenorhabditis elegans, Drosophila melanogaster, Danio rerio and Mus musculus, where mutations of cell death genes have eliminated or reduced programmed cell death in the nervous system. In many cases, genetic elimination of cell death leads to embryonic mortality or gross anatomical malformations; however, there are cases where animals develop normally but with excess neurons and glia in the nervous system. Undead cells either differentiate and function as working neurons, in some instances being of smaller size, or fail to differentiate and lack normal connections with their targets. Changes in motor control and sensory processing are generally not observed, except for during the most complex of behaviors. Examination of organisms where death genes have been genetically eliminated reveals that programmed cell death may play an important role in sculpting gross brain structure during early development of the neural tube. In contrast, the consequences of preventing neuronal cell death at later developmental stages (e.g. during vertebrate synapse formation) are just beginning to be understood.

Animals↗
PubMed2004

An extensive microarray analysis of AAL-toxin-induced cell death in Arabidopsis thaliana brings new insights into the complexity of programmed cell death in plants.

A T-DNA knockout of the Arabidopsis homologue of the tomato disease resistance gene Asc was obtained. The asc gene renders plants sensitive to programmed cell death (PCD) triggered by the fungal AAL toxin. To obtain more insights into the nature of AAL-toxin-induced cell death and to identify genes of potential importance for PCD, we carried out transcription profiling of AAL-toxin-induced cell death in this knockout with an oligonucleotide array representing 21,500 Arabidopsis genes. Genes responsive to reactive oxygen species (ROS) and ethylene were among the earliest to be upregulated, suggesting that an oxidative burst and production of ethylene played a role in the activation of the cell death. This notion was corroborated by induction of several genes encoding ROS-generating proteins, including a respiratory burst oxidase and germin oxalate oxidase. Cytochemical studies confirmed the oxidative burst and, in addition, showed synthesis of callose, a feature of the hypersensitive response. A diverse group of transcription factors was also induced. These events were followed by repression of most of the auxin-regulated genes known to be involved in growth and developmental responses. All photosynthesis-related genes were repressed. Blocking the synthesis of ethylene or NO significantly compromised cell death. In addition, we identified a heterogeneous group of early-induced genes, some of them never before associated with PCD. The group of early-induced genes included a number of proteases that were previously implicated in developmentally regulated types of PCD, suggesting a more principal role for these proteases in the PCD process. These findings provide new insights into the molecular mechanisms of plant PCD.

Apoptosis↗
PubMed1996

BMP-2/-4 mediate programmed cell death in chicken limb buds.

During limb development, the mesenchymal cells in restricted areas of limb bud, anterior necrotic zone, posterior necrotic zone, opaque zone and interdigital necrotic zones, are eliminated by programmed cell death. The transcripts of bone morphogenetic protein (Bmp)-2 and -4 were first detected in the areas where cell death was observed, then showed overlapping expression with the programmed cell death zones except the opaque zone. To investigate the function of BMP-2 and BMP-4 during limb pattern formation, the dominant negative form of BMP receptor was overexpressed in chick leg bud via a replication-competent retrovirus to block the endogenous BMP-2/-4 signaling pathway. This resulted in excess web formation at the anterior and posterior regions of limb buds in addition to marked suppression of the regression of webbing at the interdigital regions. Significant reductions in the number of apoptotic cells in these three necrotic zones were found in the limb buds which received the virus carrying dominant negative BMP receptor. This indicates that extra tissue formation is due to suppression of programmed cell death in the three necrotic zones. Moreover, BMP-2/-4 protein induced apoptosis of mesenchymal cells isolated from the interdigital region in vitro. Other TGFbeta family proteins as TGFbeta1 and Activin did not show this effect. These results suggest that BMP-2 and BMP-4 are the apoptotic signal molecules of the programmed cell death process in the chick limb buds.

Animals↗
PubMed1999

Genetic control of programmed cell death in the nematode Caenorhabditis elegans.

Studies of the development of the nematode Caenorhabditis elegans established that programmed cell death involves specific genes and proteins and that those genes and proteins act within the cells that die. This finding revealed that cell death is a fundamental and active biological process, much like cell division and cell differentiation. The characterization of genes responsible for programmed cell death in C. elegans has defined a molecular genetic pathway. This pathway is conserved evolutionarily and provides a basis for understanding programmed cell death in more complex organisms, including humans. Knowledge of the mechanisms of programmed cell death should help lead to new methods for the diagnosis and treatment of human diseases characterized by too many or too few cell deaths, including cancer.

Animals↗
PubMed1992

Programmed cell death in an estrogen-independent human breast cancer cell line, MDA-MB-468.

Previous studies have demonstrated that estrogen-responsive human breast cancer cells can be induced to undergo an energy-dependent, genetically programmed series of biochemical changes that result in the active suicide of the cells following estrogen ablation. In contrast, estrogen-independent human breast cancer cells do not activate this programmed cell death pathway following estrogen ablation. This could be due either to the absence of the cellular machinery required for programmed cell death or simply to the inability of estrogen ablation to activate this machinery. To discriminate between these two possibilities, the MDA-MB-468 estrogen-independent human mammary adenocarcinoma cell line was used as a model system to study the mechanism of cell death following cytotoxic drug treatment. Exposure of these cells to the fluorinated pyrimidines, 5-fluoro-2'-deoxyuridine or trifluorothymidine, resulted in growth inhibition and loss of proliferative capacity within 24 h. These changes occurred while cell membrane integrity was intact as measured by either cellular morphology or trypan blue exclusion. After 48 h of drug treatment, loss of cell membrane integrity was followed by cell lysis and a rapid decline in cell number. The addition of 16 microM thymidine prior to drug treatment prevented cell death, but thymidine did not rescue these cells once drug treatment was initiated. Analysis of DNA revealed the characteristic fragmentation into nucleosomal oligomers that is a hallmark of programmed cell death. Associated with this death pathway was a 15-fold induction of transforming growth factor beta 1 gene expression that has been previously observed in a variety of cellular systems undergoing programmed cell death. These results indicate that MDA-MB-468 estrogen-independent human mammary carcinoma cells retain the ability to undergo programmed cell death after treatment with cytotoxic drugs that induce a "thymineless" state.

Breast Neoplasms↗
PubMed1994

Nerve growth factor and epidermal growth factor rescue PC12 cells from programmed cell death induced by etoposide: distinct modes of protection against cell death by growth factors and a protein-synthesis inhibitor.

A rat pheochromocytoma cell line (PC12 cells) died within 24 h in the presence of etoposide (1-40 micrograms/ml), an inhibitor of topoisomerase II. This cytotoxic effect was prevented by either nerve growth (NGF) or epidermal growth factor (EGF). Cycloheximide and actinomycin D also suppressed the cell death as well. Furthermore, a difference among protective modes against etoposide-induced death by growth factors and a protein-synthesis inhibitor was observed: the protective effect of either NGF or EGF remained rather constant as a function of incubation time with etoposide whereas that of cycloheximide declined. These results indicate that etoposide induces programmed death in PC12 cells and that prevention of the programmed cell death by both NGF and EGF is mainly due to inactivation of molecules involved in the death processes rather than suppression of specific protein and/or mRNA synthesis.

Animals↗
PubMed2000

Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death.

The Caenorhabditis elegans Bcl-2-like protein CED-9 prevents programmed cell death by antagonizing the Apaf-1-like cell-death activator CED-4. Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos, in which most cells survive. By contrast, in embryos in which cells had been induced to die, CED-4 assumed a perinuclear localization. CED-4 translocation induced by the cell-death activator EGL-1 was blocked by a gain-of-function mutation in ced-9 but was not dependent on ced-3 function, suggesting that CED-4 translocation precedes caspase activation and the execution phase of programmed cell death. Thus, a change in the subcellular localization of CED-4 may drive programmed cell death.

Amino Acid Substitution↗
PubMed1996

Polyamine analogue induction of programmed cell death in human lung tumor cells.

The naturally occurring polyamines putrescine, spermidine, and spermine are required for cell growth. Based on this requirement, several polyamine analogues that interfere with polyamine function and metabolism have been synthesized as antineoplastic agents. The symmetrically substituted N1,N12-bis(ethyl)spermine (BESpm), and unsymmetrically substituted N1-ethyl-N11-[(cyclopropyl)methyl]-4, 8-diazaundecane (CPENSpm) have previously been shown to cause rapid cytotoxicity of NCI H157 cells, with concurrent high induction of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase. However, the precise mechanism(s) of the cytotoxic action of the compounds is not known. We now demonstrate that treatment with either BESpm or CPENSpm results in morphological and biochemical changes consistent with the activation of programmed cell death pathways, and that the unsymmetrically substituted CPENSpm more rapidly activates the death program. These studies suggest that the cell type-specific cytotoxicity of these polyamine analogues may be a result of their ability to selectively activate the cell death pathway in sensitive phenotypes and indicate that the relationship between the structure of the polyamine analogues and the ability to induce programmed cell death should be investigated.

Antineoplastic Agents↗
PubMed1993

Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: Cells die by one of two mechanisms, necrosis or programmed cell death. Necrosis has been implicated in stroke and occurs when the cytoplasmic membrane is compromised. Programmed cell death requires protein synthesis and often involves endonucleolytic cleavage of the cellular DNA. We assessed the potential contribution of programmed cell death to ischemia-induced neuronal death. METHODS: Cycloheximide (protein synthesis inhibitor; 1 mg/kg per 24 hours) or vehicle (1 mL/kg per 24 hours) was continuously infused into the right cerebral ventricle of spontaneously hypertensive rats. Neocortical focal ischemia was produced by tandem occlusion of the right common carotid artery and the ipsilateral middle cerebral artery. After 24 hours the brain was stained with 2% 2,3,5-triphenyltetrazolium and the ischemic zone quantitated. Protein synthesis was determined by [3H]methionine incorporation into acid-precipitated protein. DNA integrity was determined in isolated DNA by gel electrophoresis and in whole cells by flow cytometry. RESULTS: Continuous cycloheximide infusion caused approximately 70% reduction in cortical protein synthesis. Cycloheximide also reduced the size of the infarction produced by focal cerebral ischemia when compared with controls (ischemic brain volume, 147.5 +/- 25.9 and 188.7 +/- 16.8 mm3 for cycloheximide and saline, respectively; P < .01), suggesting that protein synthesis may contribute to cell death. Purified DNA from the ischemic zone showed evidence of endonucleolytic degradation when fractionated by gel electrophoresis. Flow cytometric analysis demonstrated increased propidium iodide fluorescence in intact cells isolated from ischemic cortex, indicating an increased accessibility of degraded DNA to the intercalating dye. CONCLUSIONS: New protein synthesis appears to contribute to ischemic cell death in which endonucleolytic DNA degradation is apparent. These observations implicate programmed cell death in ischemic injury and may open unique therapeutic approaches for the preservation of neurons in stroke.

Animals↗
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↗