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At least 19 recordsLinked to original sources
PubMed2001

Tumor cell "dead or alive": caspase and survivin regulate cell death, cell cycle and cell survival.

Cell death and cell cycle progression are two sides of the same coin, and these two different phenomenons are regulated moderately to maintain the cellular homeostasis. Tumor is one of the disease states produced as a result of the disintegrated regulation and is characterized as cells showing an irreversible progression of cell cycle and a resistance to cell death signaling. Several investigations have been performed for the understanding of cell death or cell cycle, and cell death research has remarkably progressed in these 10 years. Caspase is a nomenclature referring to ICE/CED-3 cysteine proteinase family and plays a central role during cell death. Recently, several investigations raised some possible hypotheses that caspase is also involved in cell cycle regulation. In this issue, therefore, we review the molecular basis of cell death and cell cycle regulated by caspase in tumor, especially hepatocellular carcinoma cells.

Animals↗
PubMed2002

Effects of excess thyroid hormone on cell death, cell proliferation, and new neuron incorporation in the adult zebra finch telencephalon.

Widespread telencephalic neuronal replacement occurs throughout life in birds. We explored the potential relationship between thyroxine (T4) and cell turnover in the adult male zebra finch. We found that many cells in the zebra finch brain, including long-projection neurons in the high vocal center (HVC), stained positively with an antibody to thyroid hormone receptors (TR). Labeling was generally weak in the ventricular zone (VZ) that gives rise to new neurons but some proliferative VZ cells and/or their progeny, identified by [3H]-thymidine labeling, co-labeled with anti-TR antibody. Acute T4 treatment dramatically increased the number of pyknotic and TUNEL-positive cells in HVC and other telencephalic regions. In contrast, degenerating cells were never observed in the archistriatum or sub-telencephalic regions, suggesting that excess T4 augments cell death selectively in regions that show naturally occurring neuronal turnover. VZ mitotic activity was not altered shortly after acute T4 treatment at a dosage that stimulated cell death, although [3H]-labeling intensity per cell was slightly reduced. Moreover, the incorporation rates for neurons formed shortly before or after acute hormone treatment were no different from control values. Chronic T4 treatment resulted in a reduction in the total number of HVC neurons. Thus, hyperthyroidism augmented neuronal death, which was not compensated for by neuronal replacement. Collectively, these results indicate that excess T4 affects adult neuronal turnover in birds, and raises the possibility that thyroxine plays an important role in the postnatal development of the avian brain and vocal behavior.

Analysis of Variance↗
PubMed1997

Cell death, cell proliferation, and estimates of hair cell life spans in the vestibular organs of chicks.

We have examined the level of on-going cell death in the chick vestibular epithelia using the TUNEL method and compared this to the rate of on-going cell proliferation. Utricles contained 22.6 +/- 6.8 TUNEL-labeled cells (mean +/- s.e.m.) while saccules contained 15.1 +/- 4.0, with approximately 90% being labeled hair cells. In separate experiments, chicks were given a single injection of BrdU and killed 2 h later. Utricles contained 116.9 +/- 6.5 BrdU-labeled cells (mean +/- s.e.m.) and saccules contained 41.0 +/- 2.2. After 24 h in culture, utricles treated with 1 mM neomycin contained 115.5 +/- 38.9 TUNEL-labeled cells, an increase of 270% over controls. After 48 h, neomycin-treated saccules contained 40.9 +/- 7.8, an increase of 152% over controls. The majority of labeled cells were in the hair cell layer. Thus, neomycin exposure results in an apoptotic death of hair cells. The in vivo data measured here were used to estimate that the average life span of utricular hair cells in young chickens is approximately 20 days, in sharp contrast to the life spans assumed for hair cells in humans.

Animals↗
PubMed2000

Cell birth, cell death, cell diversity and DNA breaks: how do they all fit together?

Substantial death of migrating and differentiating neurons occurs within the developing CNS of mice that are deficient in genes required for repair of double-stranded DNA breaks. These findings suggest that large-scale, yet previously unrecognized, double-stranded DNA breaks occur normally in early postmitotic and differentiating neurons. Moreover, they imply that cell death occurs if the breaks are not repaired. The cause and natural function of such breaks remains a mystery; however, their occurrence has significant implications. They might be detected by histological methods that are sensitive to DNA fragmentation and mistakenly interpreted to indicate cell death when no relationship exists. In a broader context, there is now renewed speculation that DNA recombination might be occurring during neuronal development, similar to DNA recombination in developing lymphocytes. If this is true, the target gene(s) of recombination and their significance remain to be determined.

Animals↗
PubMed2006

Conformational diseases and ER stress-mediated cell death: apoptotic cell death and autophagic cell death.

The expanded polyglutamine (polyQ) tracts observed in autosomal dominant neurodegenerative disorders have the tendency to form intracellular aggregates, thus enhancing apoptotic cell death and the formation of autophagic vesicles. PolyQ accumulation inhibits the ER-associated degradation system (ERAD) resulting in reduced retrotranslocation from the ER and increased accumulation of misfolded proteins in the lumen of ER. Autophagy is an early cellular defense mechanism associated with ER stress, but prolonged ER stress may induce autophagic cell death, with destruction of cellular components and apoptotic cell death. Endoplasmic reticulum (ER) stress may be the key signal for both of these events.

Animals↗
PubMed1993

Toward an understanding of the molecular mechanisms of physiological cell death.

Cell death is a normal physiological process. Morphological studies have shown that cells that die by physiological mechanisms often undergo characteristic changes termed "apoptosis" or "programmed cell death." Recent work has begun to unravel the molecular mechanisms of these deaths and has shown that one of the primary cell-death pathways is conserved throughout much of evolution. In the nematode Caenorhabditis elegans programmed cell deaths are mediated by a mechanism controlled by the ced-9 gene; in mammals apoptosis can often be inhibited by expression of the bcl-2 gene. The ability of the human BCL2 gene to prevent cell deaths in C. elegans strongly suggests that bcl-2 and ced-9 are homologous genes. Although the process of cell death controlled by bcl-2 can occur in many cell types, there appears to be more than one physiological cell-death mechanism. Targets of cytotoxic T cells and cells deprived of growth factor both exhibit changes characteristic of apoptosis, such as DNA degradation. However, bcl-2 expression protects cells from factor withdrawal but fails to prevent cytotoxic T-cell killing. DNA degradation is, thus, not specific for any one cell-death mechanism. The ability of bcl-2 to protect cells from a wide variety of pathological, as well as physiological, stimuli indicates that many triggers can serve to activate the same suicide pathway, even some thought to cause necrosis, and not physiological cell death.

Animals↗
PubMed2000

CpG-specific common commitment in caspase-dependent and -independent cell deaths.

Cell death in mammals seems to have caspase-dependent and -independent pathways unlike that in Caenorhabditis elegans where CED-3 protease activation is the central command. A recent suggestion to define apoptosis as the caspase-dependent or caspase-committed cell death form and leave cell death committed by other pathways as just cell death was meant to categorize the apparent divergence in mammalian cell death pathways. However, we show CpG oligonucleotides (ODN) blocking caspase-dependent fas(CD95) ligand-mediated apoptosis as well as caspase-independent etoposide-mediated apoptosis and etoposide-zVAD-mediated necrosis. CpG specificity was demonstrated by reversing the CpG motif or replacing it with a methylated motif (mCpG) which failed to inhibit. CpG ODN blocked CpG-specific DNA cleavage by rare-cutting NotI restriction, which produced a megabase cleavage pattern similar to that in the fasL and etoposide cell death inductions. CpG ODN inhibition was similar to that by CpG-specific SssI methylase. A common CpG-specific commitment point preceding caspase-dependent and -independent cell death pathways was suggested. CpG-specific modulation is a key epigenetic mechanism in genomic imprinting, resisting nuclease restriction, and patterning of chromatin conformations. It is now shown to have a powerful effect modulating cell death.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Caspase-like protease involvement in the control of plant cell death.

Cell death as a highly regulated process has now been recognized to be an important, if not essential, pathway that is ubiquitous in all multicellular eukaryotes. In addition to playing key roles in the morphogenesis and sculpting of the organs to give rise to highly specialized forms and shapes, cell death also participates in the programmed creation of specialized cell types for essential functions such as the selection of B cells in the immune system of mammals and the formation of tracheids in the xylem of vascular plants. Studies of apoptosis, the most well-characterized form of animal programmed cell death, have culminated in the identification of a central tripartite death switch the enzymatic component of which is a conserved family of cysteine proteases called caspases. Studies in invertebrates and other animal models suggest that caspases are conserved regulators of apoptotic cell death in all metazoans. In plant systems, the identities of the main executioners that orchestrate cell death remain elusive. Recent evidence from inhibitor studies and biochemical approaches suggests that caspase-like proteases may also be involved in cell death control in higher plants. Furthermore, the mitochondrion and reactive oxygen species may well constitute a common pathway for cell death activation in both animal and plant cells. Cloning of plant caspase-like proteases and elucidation of the mechanisms through which mitochondria may regulate cell death in both systems should shed light on the evolution of cell death control in eukaryotes and may help to identify essential components that are highly conserved in eukaryotes.

Apoptosis↗
PubMed1989

Proteolysis and cell death.

Cell death can occur by a number of different mechanisms, some of which are associated with significant protein degradation. L-cells in monolayer culture were labelled with 14C-leucine and 3H-thymidine and placed in a cold chase medium for each experiment. General cellular necrosis, induced by either repeated freeze-thawing or NaCN, rapidly disrupted cellular structure, but produced only small amounts of acid soluble 14C over a period of 24 h. Selective cell death was produced by adding 5 mM thymidine to growing tissue cultures. With such treatment, cell death became manifest only after a 24 h lag period and progressively more intense in the next 48 h. The process was characterized first by cellular enlargement and protein accumulation, followed by the formation and release of eosinophilic hyaline bodies from cell cytoplasm. These bodies were often found adjacent to the plasma membranes of viable cells, as well as within cellular vacuoles. Biochemical studies indicated that proteolysis was significantly increased; this proteolysis, but not cell death, was prevented by NH4Cl. Cell death, formation of eosinophilic hyaline bodies, and proteolysis were prevented by cycloheximide. Cell cultures that manifest cell turnover, i.e. selective cell death, apoptosis-type, will show increased amounts of vacuolar proteolysis, which may be confused with accelerated protein turnover occurring in the vacuolar system.

Ammonium Chloride↗
PubMed2004

Granzyme M mediates a novel form of perforin-dependent cell death.

Cell death is mediated by cytotoxic lymphocytes through various granule serine proteases released with perforin. The unique protease activity, restricted expression, and distinct gene locus of granzyme M suggested this enzyme might have a novel biological function or trigger a novel form of cell death. Herein, we demonstrate that in the presence of perforin, the protease activity of granzyme M rapidly and effectively induces target cell death. In contrast to granzyme B, cell death induced by granzyme M does not feature obvious DNA fragmentation, occurs independently of caspases, caspase activation, and perturbation of mitochondria and is not inhibited by overexpression of Bcl-2. These data raise the likelihood that granzyme M represents a third major and specialized perforin-dependent cell death pathway that plays a significant role in death mediated by NK cells.

Animals↗
PubMed2001

Mouse models of cell death.

Cell death is critical for the development and orderly maintenance of cellular homeostasis in metazoans. Developmental genetics in model systems, including Caenorhabditis elegans and Drosophila melanogaster, have helped to identify and order the components of cell-death pathways. An even more complex network of apoptotic pathways has evolved in higher organisms that possess homologs within each set of cell-death regulators. Whereas biochemical studies provide details of molecular mechanisms, genetic models reveal the essential physiologic roles. Transgenic and gene-ablated mice have helped to elucidate mammalian apoptotic pathways and identify the principal effect of each cell death regulator. Here, we review the details of the apoptotic machinery as revealed by mice deficient in critical components of cell-death pathways; we concentrate on cell-death regulators classified as members of the caspase and Bcl2 families or, broadly, as adaptors and mitochondrial released factors.

Animals↗
PubMed1988

Why study mechanisms of cell death?

Cell death plays a variety of important roles in biology, both physiological and pathological. Physiological cell death is an important part of development, cell turnover and various aspects of immunological defenses. Pathological cell death is an element of some of the most important diseases plaguing modern society. Recent studies on the mechanisms of calcium-mediated cell death, thought to be important for both physiological and pathological cell death, have indicated that it is a multi-step process in which the cells are active participants, triggering their own self-destruction. Such mechanisms suggest the potential for pharmacological intervention, either to prevent disease-induced tissue death or to remove unwanted tissues.

Animals↗
PubMed2005

Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death.

Autophagic cell death is characterized by the accumulation of vacuoles in physiological and pathological conditions. However, its molecular event is unknown. Here, we show that Atg5, which is known to function in autophagy, contributes to autophagic cell death by interacting with Fas-associated protein with death domain (FADD). Down-regulation of Atg5 expression in HeLa cells suppresses cell death and vacuole formation induced by IFN-gamma. Inversely, ectopic expression of Atg5 using adenoviral delivery induces autophagic cell death. Deletion mapping analysis indicates that procell death activity resides in the middle and C-terminal region of Atg5. Cells harboring the accumulated vacuoles triggered by IFN-gamma or Atg5 expression become dead, and vacuole formation precedes cell death. 3-Methyladenine or expression of Atg5(K130R) mutant blocks both cell death and vacuole formation triggered by IFN-gamma, whereas benzyloxycarbonyl-VAD-fluoromethyl ketone (Z-VAD-fmk) inhibits only cell death but not vacuole formation. Atg5 interacts with FADD via death domain in vitro and in vivo, and the Atg5-mediated cell death, but not vacuole formation, is blocked in FADD-deficient cells. These results suggest that Atg5 plays a crucial role in IFN-gamma-induced autophagic cell death by interacting with FADD.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Morphological features of cell death.

Cell death is discriminated into two main forms: apoptosis and necrosis. In contrast to necrosis, apoptosis is a regulated, energy-dependent form of cell death leading to phagocytosis of cellular remnants by neighboring cells. Characteristic morphological features of these two forms of cell death will be discussed and correlated to underlying molecular mechanisms.

Animals↗
PubMed2003

Uncoupling cell shrinkage from apoptosis reveals that Na+ influx is required for volume loss during programmed cell death.

Cell shrinkage, or the loss of cell volume, is a ubiquitous characteristic of programmed cell death that is observed in all examples of apoptosis, independent of the death stimulus. This decrease in cell volume occurs in synchrony with other classical features of apoptosis. The molecular basis for cell shrinkage during apoptosis involves fluxes of intracellular ions including K+, Na+, and Cl-. Here we show for the first time that these ion fluxes, but not cell shrinkage, are necessary for apoptosis. Using sodium-substituted medium during anti-Fas treatment of Jurkat cells, we observed cellular swelling, a property normally associated with necrosis, in contrast to the typical cell shrinkage. Surprisingly, these swollen cells displayed all of the other classical features of apoptosis, including chromatin condensation, externalization of phosphatidylserine, caspase activity, poly(ADP)-ribose polymerase cleavage, and internucleosomal DNA degradation. These swollen cells had a marked decrease in intracellular potassium, and subsequent inhibition of this potassium loss completely blocked apoptosis. Reintroduction of sodium ions in cell cultures reversed this cellular swelling, resulting in a dramatic loss of cell volume and the characteristic apoptotic morphology. Additionally, inhibition of sodium influx using a sodium channel blocker saxitoxin completely prevented the onset of anti-Fas-induced apoptosis in Jurkat cells. These findings suggest that sodium influx can control not only changes in cell size but also the activation of apoptosis, whereas potassium ion loss controls the progression of the cell death process. Therefore cell shrinkage can be separated from other features of apoptosis.

Adenosine Triphosphate↗
PubMed1988

Programmed cell death: dying cells synthesize a co-ordinated, unique set of proteins in two different episodes of cell death.

Intersegmental muscles of the tobacco hornworm, Manduca sexta, degenerate promptly after the ecdysis of the moth. Protein content of the growing, static, and degenerating muscle was evaluated by two-dimensional electrophoresis; RNA was isolated from the muscle and translated, and the translation products likewise analyzed by two-dimensional electrophoresis. Growing and static muscles synthesize predominantly myofibrillar proteins, and small cytosolic proteins constitute a vanishingly small proportion of the proteins identified even by silver staining. When the muscle begins to degenerate, a large number of smaller proteins is seen on the gels. Many of these are apparently fragments of the myofibrillar proteins, but over 30 can be recognized as new translation products. Most of the translation products are found in two regions, one ranging from 20 to 40 kDa and with a pI of 6.5-6.9; and the other approx. 50-70 kDa and pI 5.8-6.2. The pattern is identical in two separate instances of degeneration.

Aging↗
PubMed2005

Mitochondria: pharmacological manipulation of cell death.

Cell death by apoptosis or necrosis is often important in the etiology and treatment of disease. Since mitochondria play important roles in cell death pathways, these organelles are potentially prime targets for therapeutic intervention. Here we discuss the mechanisms through which mitochondria participate in the cell death process and also survey some of the pharmacological approaches that target mitochondria in various ways.

Animals↗