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PubMed2006

Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population.

The PD-1 (programmed death 1) molecule is a negative regulator of T cells. PDCD1 (programmed cell death 1) has been reported to have a genetic association in systemic lupus erythematosus and rheumatoid arthritis in Caucasians. However, there are no reports on the association between this gene and ankylosing spondylitis (AS). The present study investigated the association of the PD-1 polymorphisms and the haplotypes with AS in a Korean population sample. In a case-control association study, two single-nucleotide polymorphisms, PD-1.5 C/T and PD-1.9 T/C, were genotyped in 95 AS patients and 130 healthy controls. The T allele of the PD-1.9 polymorphism was more frequent in the Korean male population with AS than in the Korean male controls (21.0% versus 6.9%, odds ratio 1.89, 95% confidence interval 1.483 to 2.408). The frequency of the CT haplotype (PD-1.5 C/T and PD-1.9 T/C) was higher in the AS patients (19%) than the controls (5.4%) (odds ratio 1.83, 95% confidence interval 1.559 to 2.521). The PD-1 polymorphism was demonstrated in Korean AS patients. The results suggest a genetic association between the PD-1 polymorphism and susceptibility to AS.

Adult↗
PubMed2000

Kainic acid-induced seizures produce necrotic, not apoptotic, neurons with internucleosomal DNA cleavage: implications for programmed cell death mechanisms.

Prolonged seizures (status epilepticus) induced by kainic acid activate programmed cell death mechanisms, and it is believed that kainic acid-induced status epilepticus induces neuronal apoptosis. In order to test this hypothesis, adult rats were subjected to 3-h kainic acid-induced seizures, with 24- or 72-h recovery periods. Neuronal death was assessed by light microscopy with the Hematoxylin and Eosin stain and with in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL stain), by electron microscopy, and by agarose gel electrophoresis of DNA extracted from five vulnerable brain regions. Spontaneous and MK-801-induced apoptotic neurons from retrosplenial cortex of neonatal rats, evaluated by light and electron microscopy, were used as positive controls for apoptosis. Surprisingly, the large chromatin clumps of apoptotic neurons were TUNEL negative, whereas the cytoplasm showed light-to-moderate TUNEL staining, consistent with a lack of identifiable nuclear membranes ultrastructurally, and with intermingling of nuclear and cytoplasmic contents. Ultrastructurally, the acidophilic neurons produced by kainic acid-induced status epilepticus, identified with Hematoxylin and Eosin stain, were dark, shrunken and necrotic, with pyknotic nuclei containing small, dispersed chromatin clumps, and with cytoplasmic vacuoles, some of which were swollen, disrupted mitochondria. No apoptotic cells were seen. Acidophilic neurons were found in up to 20 of 23 brain regions examined and comprised 10-25% of the total number of neurons examined. A subset of these neurons (<10% of the total number of neurons in five of 23 regions) had TUNEL-positive nuclei 72h but not 24h after status epilepticus. Internucleosomal DNA cleavage (DNA "laddering") occurred in the four most damaged brain regions examined by electron microscopy 24h after SE and the three most damaged regions 72h after status epilepticus. Our results demonstrate that kainic acid-induced status epilepticus produces neuronal necrosis and not apoptosis in adult rats. The necrotic neurons show nuclear pyknosis, chromatin condensation and DNA laddering. Programmed cell death mechanisms activated by kainic acid-induced status epilepticus occur in neurons which become necrotic and could contribute to necrotic, as well as apoptotic, neuronal death.

Animals↗
PubMed2004

Limited role of developmental programmed cell death pathways in Drosophila norpA retinal degeneration.

We examined the role of programmed cell death (PCD) pathways in retinal degeneration caused by a mutation in the norpA gene. norpA degeneration shows morphological hallmarks of programmed cell death, specifically cytoplasmic condensation and engulfment of the dying photoreceptor cells by neighboring retinal pigment cells. However, genetic mosaic analysis of adult photoreceptors lacking rpr, hid, and grim show that these PCD inducers are not required for norpA degeneration. We showed previously that ectopic expression of either rpr or hid triggers rapid PCD in adult photoreceptors, and this is completely suppressed by the coexpression of the baculoviral P35 caspase inhibitor. In contrast, expression of P35 does not suppress norpA retinal degeneration, although a small delay in the rate of degeneration is observed in low light-low temperature conditions. P35 does not alter the morphological characteristics of norpA cell death. Overexpression of the Drosophila inhibitor of apoptosis Diap1 or a dominant-negative form of the Dronc caspase, even when coexpressed with P35, does not dramatically alter the time course of norpA degeneration. These results establish that the pathways responsible for PCD in development do not play a major role in adult retinal degeneration caused by norpA.

Animals↗
PubMed2000

Dihydrotestosterone stimulates branching morphogenesis, cell proliferation, and programmed cell death in mouse embryonic lung explants.

Early gestation lung development is characterized by branching morphogenesis of the airways and basic lung structure formation. Androgens delay late-gestation lung development if the androgen exposure begins in early gestation. We hypothesized that there would be effects of early gestation androgens on lung development. Embryonic mouse lungs (d 11.5) were cultured with dihydrotestosterone (DHT), DHT plus flutamide, or with nothing as controls. Branching morphogenesis was significantly increased after 24, 48, and 72 h of culture. This effect was blocked by simultaneous flutamide treatment. Fetal sex did not influence the DHT response. DHT increased cell proliferation as measured by [3H]thymidine incorporation into DNA. Autoradiography showed prominent [3H]thymidine labeling of epithelia and mesenchyme in regions of new bud formation. DHT treatment significantly increased the thymidine-labeling index of fibroblasts and airway epithelial cells. Programmed cell death, which is found in developing organs in association with cell proliferation during structure formation and tissue remodeling, was studied using terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling assay. In control lungs, programmed cell death occurred in the peripheral mesenchyme surrounding newly forming buds and underlying airway branch points. DHT treatment increased programmed cell death in association with increased branching morphogenesis. Evaluation of near-adjacent sections (control and DHT-treated lungs) showed that apoptotic mesenchymal cells were flanked by [3H]thymidine-labeled fibroblasts and epithelial cells, suggesting a coordination of these processes in the progression of branching morphogenesis. We conclude that androgen enhances the process of early lung morphogenesis by increasing cell proliferation and programmed cell death and by promoting the structural progression of branching morphogenesis.

Animals↗
PubMed1998

Expression of p75NTR in a human prostate epithelial tumor cell line reduces nerve growth factor-induced cell growth by activation of programmed cell death.

Epithelial expression of the 75-kDa low-affinity neurotrophin receptor (p75NTR) is inversely associated with the malignant progression of the human prostate. To elucidate the function of p75NTR in the prostate, the human prostate epithelial tumor cell line TSU-pr1, which does not express p75NTR, was stably and transiently transfected with the cDNA for the receptor. The stably transfected cells were assessed for levels of p75NTR expression and categorized into low, intermediate, and high receptor-expressing clones by immunocytochemical and immunoblot analyses. Incorporation of [3H]thymidine was used to assess nerve growth factor (NGF)-induced changes in cell proliferation. TSU-pr1 epithelial cells transfected with a neomycin-resistance vector alone demonstrated a dose-dependent increase in the rate of NGF-stimulated [3H]thymidine uptake. Expression of p75NTR decreased the dose-dependent NGF-mediated proliferation of the TSU-pr1 prostate epithelial cells. The greater the degree of expression of p75NTR in the transfected clones, the less the stimulatory effect of exogenous NGF on cell proliferation. Furthermore, the ratio of p75NTR to tropomyosin receptor kinase for each clone was inversely correlated with the ability of NGF to stimulate growth of the TSU-pr1 transfectants. To determine whether p75NTR-mediated growth inhibition of prostate epithelia occurs by induction of programmed cell death, transiently transfected clones were analyzed by an in situ DNA nick-translation assay. NGF deprivation and anti-NGF treatment of transiently transfected TSU-pr1 cells significantly increased the proportion of epithelial cells undergoing programmed cell death by approximately fourfold above control levels. Conversely, addition of NGF was able to rescue p75NTR-expressing clones from undergoing programmed cell death at levels not significantly different from those of mock-transfected clones. These results demonstrate that p75NTR is a negative regulator of human prostate epithelial cell growth by induction of programmed cell death. Hence, loss of p75NTR expression in human prostate epithelia eliminates a growth-inhibitory pathway, thereby contributing to the malignant progression of the prostate.

Apoptosis↗
PubMedDate not supplied

Induction of programmed cell death (apoptosis) in human lymphoid leukemia cells by catechin compounds.

The need for antitumor compounds with novel mechanisms of action is great. The exposure of human lymphoid leukemia Molt 4B cells to epigallocatechin (EGC), epigallocatechin gallate (EGCG), and persimmon extract (PS) led to both growth inhibition and the induction of programmed cell death (apoptosis). The fragmentation of DNA to oligonucleosomal-sized fragments, characteristic of programmed cell death, was determined to be concentration- and time-dependent. These data provide the first evidence that catechin compounds and persimmon extract containing all these catechin compounds induce programmed cell death.

Apoptosis↗
PubMed2002

Cell death in Leishmania induced by stress and differentiation: programmed cell death or necrosis?

Unicellular organisms, such as the protozoan parasite Leishmania, can be stimulated to show some morphological and biochemical features characteristic of mammalian apoptosis. This study demonstrates that under a variety of stress conditions such as serum deprivation, heat shock and nitric oxide, cell death can be induced leading to genomic DNA fragmentation into oligonucleosomes. DNA fragmentation was observed, without induction, in the infectious stages of the parasite, and correlated with the presence of internucleosomal nuclease activity, visualisation of 45 to 59 kDa nucleases and detection of TUNEL-positive nuclei. DNA fragmentation was not dependent on active effector downstream caspases nor on the lysosomal cathepsin L-like enzymes CPA and CPB. These data are consistent with the presence of a caspase-independent cell death mechanism in Leishmania, induced by stress and differentiation that differs significantly from metazoa.

Animals↗
PubMed1997

Apoptosis and disease: regulation and clinical relevance of programmed cell death.

Regulation of the homeostatic balance between cell proliferation and cell death is essential for development and maintenance of multicellular organisms. Physiologic, or programmed, cell death is dependent on a genetically encoded and evolutionarily conserved pathway that induces a form of cellular suicide known as apoptosis. In the past decade, it has become clear that the regulatory mechanisms controlling programmed cell death are as fundamental, and as complex, as those regulating cell proliferation. Perturbation of the signaling cascades regulating apoptosis, whether by extracellular triggers, acquired or germline genetic mutations, or viral mimicry of signaling molecules, can result in a wide variety of human diseases. Analysis of these regulatory pathways has led to a better understanding of the etiology and pathogenesis of many human diseases, notably cancers, infectious diseases including AIDS, autoimmune diseases, and neurodegenerative/neurodevelopmental diseases. Our understanding of the regulation of programmed cell death in health and disease is far from complete, and the challenge of converting that understanding into new therapeutic modalities has only begun to be approached.

Animals↗
PubMed2003

[Relationship between programmed cell death mechanisms and neuronal necrosis induced by seizures].

OBJECTIVE: To clarify if programmed cell death mechanisms induced by seizures take part in the necrotic process of neurons. METHODS: Seizure was induced by pilocarpine (P) in Sprague-Dawley adult rats which were allowed to recover for 24 or 72 hours before perfusion-fixation. Neuronal death was assessed by light microscopy with the hematoxylin-eosin (HE) staining and with in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Bax and Bcl-2 protein expression were examined by histochemistry. RESULTS: Twenty-four and 72 hours after seizures, neuronal death in hippocampus CA1 region was morphologically necrotic. TUNEL-positive and morphologically necrotic cells increased in the hippocampal CA1 region at 72 hours after seizures, there was significant difference compared with controls (P < 0.001). Bax expression was also increased in the hippocampal CA1 region at 72 hours after seizures (P < 0.001), but Bcl-2 expression did not increase, while Bcl-2/Bax ratio decreased. CONCLUSION: Seizures induced late-onset neuronal necrosis was accompanied by programmed cell death mechanisms.

Animals↗
PubMed2005

Programmed cell death during the transition from multicellular structures to globular embryos in barley androgenesis.

Androgenesis represents one of the most fascinating examples of cell differentiation in plants. In barley, the conversion of stressed uninucleate microspores into embryo-like structures is highly efficient. One of the bottlenecks in this process is the successful release of embryo-like structures out of the exine wall of microspores. In the present work, morphological and biochemical studies were performed during the transition from multicellular structures to globular embryos. Exine wall rupture and subsequent globular embryo formation were observed only in microspores that divided asymmetrically. Independent divisions of the generative and the vegetative nuclei gave rise to heterogeneous multicellular structures, which were composed of two different cellular domains: small cells with condensed chromatin structure and large cells with normal chromatin structure. During exine wall rupture, the small cells died and their death marked the site of exine wall rupture. Cell death in the small cell domain showed typical features of plant programmed cell death. Chromatin condensation and DNA degradation preceded cell detachment and cytoplasm dismantling, a process that was characterized by the formation of vesicles and vacuoles that contained cytoplasmic material. This morphotype of programmed cell death was accompanied by an increase in the activity of caspase-3-like proteases. The orchestration of such a death program culminated in the elimination of the small generative domain, and further embryogenesis was carried out by the large vegetative domain. To date, this is the first report to show evidence that programmed cell death takes part in the development of microspore-derived embryos.

Apoptosis↗
PubMed1993

Inhibition of programmed cell death by catalase and phenylalanine methyl ester.

1. Programmed cell death proceeds by an unknown mechanism which results in characteristic morphological changes known as apoptosis. 2. We have proposed that, in hormone-induced apoptosis, cell death may be the result of an attack of cells destined to die by cytotoxic macrophages. 3. We have investigated the effects of superoxide dismutase, catalase and the macrophage toxin, phenylalanine methyl ester, on the regression of tadpole tail slices in culture. 4. Our findings, that regression of bullfrog tadpole tails is blocked by catalase and phenylalanine methyl ester, support the working hypothesis.

Animals↗
PubMed1996

X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death.

THE Bcl-2 family of proteins regulate programmed cell death by an unknown mechanism. Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-xL (ref. 2). The structures consist of two central, primarily hydrophobic alpha-helices, which are surrounded by amphipathic helices. A 60-residue loop connecting helices alpha1 and alpha2 was found to be flexible and non-essential for anti-apoptotic activity. The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity and form an elongated hydrophobic cleft that may represent the binding site for other Bcl-2 family members. The arrangement of the alpha-helices in Bcl-xL is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins. The structural similarity may provide a clue to the mechanism of action of the Bcl-2 family of proteins.

Amino Acid Sequence↗
PubMed1999

De novo programmed cell death in oral cancer.

AIM: The importance of programmed cell death or apoptosis in the maintenance of tissue homoeostasis and the pathogenesis of oral cancer was analysed in relation to apoptosis regulatory proteins, tissue proliferation and tumour histology. METHODS AND RESULTS: The extent of apoptosis was defined by morphological criteria and the TUNEL (terminal deoxy nucleotidyl transferase-mediated dUTP biotin nick end labelling) assay. p53, bax, bcl-2 and cyclin D1 expression was evaluated by immunocytochemistry. The presence of mutant p53 was analysed using a mutant p53-specific ELISA. An inverse correlation was observed between TUNEL reactivity and histology of the lesion (r = -0.555, P = 0.0001). There was also correlation between TUNEL reactivity and immunoreactivity of apoptosis regulatory proteins. p53 (r = 0.641, P = 0.00023), bcl-2 (r = -0.642, P = 0.00014) and bax (r = 0.651, P = 0.00002). The presence of mutant p53 protein showed an inverse correlation to the extent of apoptosis (r = - 0.301, P = 0.00063). Significant correlation was evident between the bax/bcl-2 ratio and TUNEL (r = 0.652, P = 0.00001) as well as between cyclin D1 and TUNEL reactivity (r = 0.577, P = 0.00001). CONCLUSIONS: Results from this study suggest that apoptosis decreases as histological abnormality increases. Apoptotic regulatory proteins are also altered in a histologically dependent manner. Deregulated proliferation occurs simultaneously with decreased apoptosis during tumour progression in the oral mucosa.

Adult↗
PubMed2006

Cryptochrome-1-dependent execution of programmed cell death induced by singlet oxygen in Arabidopsis thaliana.

Programmed cell death (PCD) plays an important role during the life cycle of higher organisms. Although several regulatory mechanisms governing PCD are thought to be conserved in animals and plants, light-dependent cell death represents a form of PCD that is unique to plants. The light requirement of PCD has often been associated with the production of reactive oxygen species during photosynthesis. In support of this hypothesis, hydrogen peroxide and superoxide have been shown to be involved in triggering a PCD response. In the present work, we have used the conditional flu mutant of Arabidopsis to analyze the impact of another reactive oxygen species, singlet oxygen, on cell death. Unexpectedly, the light-dependent release of singlet oxygen alone is not sufficient to induce PCD of flu seedlings but has to act together with a second concurrent blue light reaction. This blue-light-specific trigger of PCD could not be attributed to a photosynthetic reaction or redox change within the chloroplast but to the activation of the blue light/UVA-specific photoreceptor cryptochrome. The singlet oxygen-mediated and cryptochrome-dependent cell death response differs in several ways from PCD triggered by hydrogen peroxide/superoxide.

Apoptosis↗
PubMed1991

Extracellular ATP as a trigger for apoptosis or programmed cell death.

Extracellular ATP is shown here to induce programmed cell death (or apoptosis) in thymocytes and certain tumor cell lines. EM studies indicate that the ATP-induced death of thymocytes and susceptible tumor cells follows morphological changes usually associated with glucocorticoid-induced apoptosis of thymocytes. These changes include condensation of chromatin, blebbing of the cell surface, and breakdown of the nucleus. Cytotoxicity assays using double-labeled cells show that ATP-mediated cell lysis is accompanied by fragmentation of the target cell DNA. DNA fragmentation can be set off by ATP but not the nonhydrolysable analogue ATP gamma S nor other nucleoside-5'-triphosphates. ATP-induced DNA fragmentation but not ATP-induced 51Cr release can be blocked in cells pretreated with inhibitors of protein or RNA synthesis or the endonuclease inhibitor, zinc; whereas pretreatment with calmidazolium, a potent calmodulin antagonist, blocks both DNA fragmentation and 51Cr release. The biochemical and morphological changes caused by ATP are preceded by a rapid increase in the cytoplasmic calcium of the susceptible cell. Calcium fluxes by themselves, however, are not sufficient to cause apoptosis, as the pore-forming protein, perforin, causes cell lysis without DNA fragmentation or the morphological changes associated with apoptosis. Taken together, these results indicate that ATP can cause cell death through two independent mechanisms, one of which, requiring an active participation on the part of the cell, takes place through apoptosis.

Adenosine Triphosphate↗
PubMed2006

DNA degradation and nuclear degeneration during programmed cell death in petals of Antirrhinum, Argyranthemum, and Petunia.

Programmed cell death (PCD) was studied in the petals of Antirrhinum majus, Argyranthemum frutescens, and Petunia hybrida, using DNA degradation and changes in nuclear morphology as parameters. The petals exhibit loss of turgor (wilting) as a visible symptom of PCD. DNA degradation, as shown on agarose gels, occurred in all species studied, prior to visible wilting. The number of DNA masses in all the petals of a flower, determined by flow cytometry, markedly increased in Argyranthemum and Petunia, but decreased in Antirrhinum. Many small DNA masses were observed in Argyranthemum and Petunia. The surface of each small DNA mass stained with the lipophilic fluorochrome 3,3'-dihexyloxacarbocyanine iodide (DiOC6), indicating that these masses were surrounded by a membrane. In Antirrhinum, in contrast, the chromatin fragmented into several small spherical clumps that remained inside a large membranous structure. Nuclear fragmentation, therefore, did not occur in Antirrhinum, whereas nuclear fragmentation possibly was a cause of the small DNA masses in Argyranthemum and Petunia. It is concluded that at least two contrasting nuclear morphologies exist during PCD. In the first, the chromatin fragments inside the nucleus, not accompanied--or followed--by nuclear fragmentation. In the second, a large number of DNA masses were observed each enveloped by a membrane. The second type was probably due, at least partially, to nuclear fragmentation.

Antirrhinum↗
PubMed2003

Programmed cell death remodels lace plant leaf shape during development.

Programmed cell death (PCD) functions in the developmental remodeling of leaf shape in higher plants, a process analogous to digit formation in the vertebrate limb. In this study, we provide a cytological characterization of the time course of events as PCD remodels young expanding leaves of the lace plant. Tonoplast rupture is the first PCD event in this system, indicated by alterations in cytoplasmic streaming, loss of anthocyanin color, and ultrastructural appearance. Nuclei become terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling positive soon afterward but do not become morphologically altered until late stages of PCD. Genomic DNA is fragmented, but not into internucleosomal units. Other cytoplasmic changes, such as shrinkage and degradation of organelles, occur later. This form of PCD resembles tracheary element differentiation in cytological execution but requires unique developmental regulation so that discrete panels of tissue located equidistantly between veins undergo PCD while surrounding cells do not.

Anthocyanins↗
PubMedDate not supplied

Programmed cell death in the mouse cochleovestibular ganglion during development.

Programmed cell death (PCD) is as essential to development as is cell proliferation. Our objective was to elucidate the spatiotemporal occurrence of PCD during the development of the cochleovestibular ganglion. We performed a time-sequence study on the distribution of in situ PCD, apoptosis, during the development of the mouse cochleovestibular ganglion by using the TUNEL method to detect apoptosis histochemically. Apoptosis in the cochleovestibular ganglion was observed from the 11.5th gestational day (GD) to the 18. 5th GD. Apoptosis was seen most extensively in the vestibular ganglion cells at the 13.5th GD, while in the spiral ganglion cells apoptosis was maximal between the 15.5th and 16.5th GD. Because these times of peak apoptotic activity almost exactly corresponded to the events of innervation and terminal mitosis of the cochleovestibular ganglion cells, we infer that PCD is involved in the innervation and modulates the number of cochleovestibular ganglion cells overproduced by terminal mitosis.

Animals↗