Cell Suicide Pathway Research Articles

Genetic Aberrations in Caspase Family of Genes and Their Possible Association with HNSCC

The cell suicide pathway of apoptosis is a necessary event in the life of multicellular organisms. It is involved in many biological processes ranging from development to the immune response. Over expression of interleukin-1β-converting enzyme (later renamed caspase-1) was shown to be sufficient to induce apoptosis in mammalian cells. The present study aims to assess the gene alterations in the Caspase family of cytochromes so as to derive an association with HNSCC. Earlier eleven genes were found in the human genome to encode 11 human caspases, caspase-1 to caspase-10 and caspase-14, which is now populated to 13, whereas 10 genes were found in the mouse genome to encode 10 murine caspases including caspase-1, 2, 3, 6, 7, 8, 9, 11, 12 and 14. Caspases share a number of features distinguishable from other proteases. The analysis follows an observational study design, employing several computational tools to identify and predict the possible outcomes of gene alterations identified in HNSCC patients. cBioportal server was used to identify the gene alterations which was further analyzed using tools such as PROVEAN, I-Mutant and gnomAD. Several reported polymorphic variants were also identified. The pathogenicity and protein stability of gene alterations documented in the present study were identified at standard biological conditions. Further experimental studies would provide concrete evidence on the association of the observed genetic abnormalities with HNSCC especially in individuals exposed to habitual carcinogens.

Current questions and possible controversies in autophagy.

Interest in autophagy has exploded over the last decade, with publications highlighting crosstalk with several other cellular processes including secretion, endocytosis, and cell suicide pathways including apoptosis. Autophagy proteins have also been implicated in other cellular processes independently of their roles in autophagy, creating complexities in the interpretation of autophagy (Atg) mutant gene data. Interestingly, this self-eating process is a survival mechanism that can also promote cell death, but when and how autophagy may ‘switch’ its function is still under debate. Indeed, there are currently many models of how autophagy actually influences cell death. In this review, we highlight some outstanding questions and possible controversies in the autophagy field.

Autophagy and cell death: The jury's still out

Since the publication of seminal work in the early 1970s by John Kerr and Andrew Wyllie1, we have been aware that mammalian cells have the genetically encoded capability to give up the ghost and trigger a highly conserved cell-suicide pathway called apoptosis. Not content with this important knowledge, many researchers have spent the intervening years attempting to identify and characterize other ‘programmed cell death’ (PCD) mechanisms that might also have important roles in development and disease. One of these was ‘autophagy’, a process by which cells became vacuolated and progressively devoid of cytoplasm. Over the years, ‘autophagic cell death’ has been linked with the timely death of cells in development, as well as the catastrophic loss of cells in several important human diseases. But is autophagy truly a cell death mechanism in its own right? Perhaps it is just an innocent bystander, unfairly accused on the basis of flimsy circumstantial evidence? The jury may finally be poised to return a decisive verdict….

The soluble proteome of tobacco Bright Yellow-2 cells undergoing H₂O₂-induced programmed cell death.

Plant programmed cell death (PCD) is a genetically controlled process that plays an important role in development and stress responses. Reactive oxygen species (ROS) are key inducers of PCD. The addition of 50 mM H2O2 to tobacco Bright Yellow-2 (TBY-2) cell cultures induces PCD. A comparative proteomic analysis of TBY-2 cells treated with 50 mM H2O2 for 30 min and 3 h was performed. The results showed early down-regulation of several elements in the cellular redox hub and inhibition of the protein repair–degradation system. The expression patterns of proteins involved in the homeostatic response, in particular those associated with metabolism, were consistently altered. The changes in abundance of several cytoskeleton proteins confirmed the active role of the cytoskeleton in PCD signalling. Cells undergoing H2O2-induced PCD fail to cope with oxidative stress. The antioxidant defence system and the anti-PCD signalling cascades are inhibited. This promotes a genetically programmed cell suicide pathway. Fifteen differentially expressed proteins showed an expression pattern similar to that previously observed in TBY-2 cells undergoing heat shock-induced PCD. The possibility that these proteins are part of a core complex required for PCD induction is discussed.

A comprehensive characterization of the caspase gene family in insects from the order Lepidoptera

BackgroundThe cell suicide pathway of apoptosis is a necessary event in the life of multicellular organisms. It is involved in many biological processes ranging from development to the immune response. Evolutionarily conserved proteases, called caspases, play a central role in regulating apoptosis. Reception of death stimuli triggers the activation of initiator caspases, which in turn activate the effector caspases. In Lepidoptera, apoptosis is crucial in processes such as metamorphosis or defending against baculovirus infection. The discovery of p35, a baculovirus protein inhibiting caspase activity, has led to the characterization of the first lepidopteran caspase, Sf-Caspase-1. Studies on Sf-Caspase-1 mode of activation suggested that apoptosis in Lepidoptera requires a cascade of caspase activation, as demonstrated in many other species.ResultsIn order to get insights into this gene family in Lepidoptera, we performed an extensive survey of lepidopteran-derived EST datasets. We identified 66 sequences distributed among 27 species encoding putative caspases. Phylogenetic analyses showed that Lepidoptera possess at least 5 caspases, for which we propose a unified nomenclature. According to homology to their Drosophila counterparts and their primary structure, we determined that Lep-Caspase-1, -2 and -3 are putative effector caspases, whereas Lep-Caspase-5 and -6 are putative initiators. The likely function of Lep-Caspase-4 remains unclear. Lep-Caspase-2 is absent from the silkworm genome and appears to be noctuid-specific, and to have arisen from a tandem duplication of the Caspase-1 gene. In the tobacco hawkmoth, 3 distinct transcripts encoding putative Caspase-4 were identified, suggesting at least 2 duplication events in this species.ConclusionsThe basic repertoire of five major types of caspases shared among Lepidoptera seems to be smaller than for most other groups studied to date, but gene duplication still plays a role in lineage-specific increases in diversity, just as in Diptera and mammals.

Ceramide-induced cell death/survival in murine osteoblasts

Programmed cell death (PCD) or apoptosis is a naturally occurring cell suicide pathway induced in a variety of cell types. We determined whether ceramide treatment contributes to reduced cell viability and increased PCD in primary osteoblasts and the signalling pathways that are involved. Cell viability was determined by the 3-(4,5-dimethyl-thiozol-2-yl)-2,5-diphenyl tetrazolium bromide assay. We found that C(2)-ceramide (<or=10(-7) M) promoted osteoblast viability, whilst concentrations >or=2 x 10(-6) M significantly reduced osteoblast viability in a dose- and time-dependent manner. The effect of ceramide on cell viability was specific since C(2)-dihydroceramide had no effect. Increasing intracellular ceramide levels with either sphingomyelinase (SMase) or an inhibitor of ceramide metabolism also increased osteoblast apoptosis. Ceramide-induced PCD in osteoblasts was determined by nuclear appearance and DNA fragmentation. PCD was induced by both C(2)-ceramide and SMase. The ability of ceramide (5 x 10(-8) M) to promote osteoblast survival was prevented by a general protein kinase C (PKC) inhibitor and by a PKC zeta inhibitor, whilst osteoblast survival was enhanced in the presence of a protein phosphatase 1 (PP1) inhibitor. Phosphatidylinositol-3 kinase (PI3K) inhibitors had no effect on osteoblast survival. The ability of ceramide (5 x 10(-5) M) to induce apoptosis was prevented by the inhibitors of PP1 and PKC delta, whilst the general PKC and PI3K inhibitors had no effect on it. Our findings suggest that ceramide signals osteoblast survival and apoptosis through different intracellular pathways, and that alteration in the intracellular levels of ceramide may play an important role in bone remodelling.

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Increased Occurrence of Caspase-Dependent Apoptosis in Unfavorable Neuroblastomas

Neuroblastoma frequently shows spontaneous regression in which two distinct types of programmed cell death, ie, caspase-dependent apoptosis and H-Ras-mediated autophagic degeneration, have been suggested to play a key role. The current study was conducted to determine which of these cell suicide pathways predominated in this tumor regression. Periodic acid-Schiff (PAS) staining and immunostaining for H-Ras and for the full-length and cleaved forms of caspase-3, poly (ADP-ribose) polymerase (PARP), and lamin A were carried out on 55 archival tumor specimens. The incidence of caspase-dependent apoptosis in each tumor was quantified by cleaved lamin A staining and compared with clinicopathologic prognostic factors. Although a recent report has shown that neuroblastic cells undergoing autophagic degeneration were readily detectable by PAS and H-Ras staining, we could not confirm this result in any of our samples with the exception of one tumor. Instead, many of our neuroblastoma samples showed nonspecific PAS and Ras staining in areas of necrosis, suggesting that autophagic "degeneration" indeed corresponds to coagulation necrosis or oncosis. Unexpectedly, the incidence of caspase-dependent apoptosis was significantly correlated with indicators of a poor prognosis in these tumors, including Shimada's unfavorable histology, MYCN amplification, and a higher mitosis-karyorrhexis index, but not with factors related to tumor regression such as clinical stage and mass screening. These results indicate that neither caspase-dependent apoptosis nor autophagic "degeneration" may be involved in spontaneous neuroblastoma regression. This suggests that other mechanisms, perhaps such as tumor maturation, may be responsible for this phenomenon.

PLANT PROGRAMMED CELL DEATH, ETHYLENE AND FLOWER SENESCENCE

Programmed cell death (PCD) applies to cell death that is part of the normal life of multicellular organisms. PCD is found throughout the animal and plant kingdoms; it is an active process in which a cell suicide pathway is activated resulting in controlled disassembly of the cell. Most cases of PCD described in animal systems take the form of apoptosis, a cell death process characterised by specific features such as cell shrinkage, blebbing of the plasma membrane, condensation and fragmentation of the nucleus and internucleosomal cleavage of DNA. The final stage of apoptosis is the fragmentation of the cell into cellular debris-containing vesicles called `apoptotic bodies` that are being phagocytosed by other cells. A specific class of cell death- associated cystein proteases (caspases) has been identified. Generally, apoptotic cell death involves a sequence of caspase activation events in which initiator caspases activate down-stream executioner caspases that process a variety of target proteins eventually leading to the apoptotic phenotype. The occurrence of hallmarks of animal apoptosis was studied in tomato cells treated with the anticancer drug and inducer of apoptosis, camptothecin (cpt). It was shown that cpt-induced cell death is accompanied by nuclear condensation, the appearance of TUNEL-positive nuclei, DNA laddering and formation of DNA-containing (apoptotic) bodies and was greatly inhibited by inhibitors of animal caspases. Together the results indicate that cpt induced a cell death pathway with similarities to caspase-mediated (apoptotic) cell death in animal systems. We used cpt-treated cells to study the possible involvement of ethylene in cell death. Treatment of the cells with relatively high concentrations of ethylene did not have any effect on viability of the cells. However, when ethylene was applied in combination with cpt, a significant increase in cell death was observed as compared to cpt treatment alone. Experiments with inhibitors of ethylene production or ethylene action showed that ethylene is an essential factor mediating cpt-induced cell death. Flower senescence is accompanied by rapid death of large numbers of cells. In situ DNA degradation was studied in gypsophila petals using TUNEL. We showed that TUNEL positive nuclei appear well before the onset of the increase in ethylene production and visible signs of senescence. The role of PCD in flower senescence is discussed.

A Greasy Way to Die

Certain fatty molecules might grease the way toward death for motor neurons. According to a new study, mice and humans with amyotrophic lateral sclerosis (ALS) harbor excess lipids, which apparently activate cell death mechanisms in response to oxidative stress. The finding adds to researchers' understanding of how ALS kills neurons and might push ALS drug hunters to set their sights on lipid-producing enzymes. The debilitating disease gradually destroys motor neurons in the spinal cord, ultimately killing patients by paralyzing their lungs. ALS is not a disease of advanced age, but it appears to share neuron-destroying mechanisms with age-related degenerative diseases such as Alzheimer's. An inherited form of ALS is caused by a mutation in the antioxidant enzyme superoxide dismutase (SOD), suggesting that oxidative stress contributes to the disease; inflammation or an overload of the excitatory neurotransmitter glutamate might also play a role. Previous work suggests that cells crank out lipids called ceramides when subjected to oxidative stress; these lipids act as signaling molecules that regulate cell suicide pathways. Perhaps lipids trigger the demise of neurons in ALS, proposed neuroscientist Mark Mattson of the National Institute on Aging Gerontology Research Center in Baltimore, Maryland, and colleagues. The researchers obtained spinal cord samples from patients who had died of ALS and measured lipid concentrations. ALS samples contained more ceramides than did control tissue. Amounts of two related lipids, sphingomyelin and cholesterol esters, were also higher. To extend the finding, the team examined spinal cord samples from mice engineered to carry the SOD mutation responsible for some human familial ALS. Like their human counterparts, ALS mice had additional ceramide, sphingomyelin, and cholesterol esters. Mice that hadn't yet shown signs of the disease were also laden with lipids, suggesting that the fatty molecules contribute to the disease at its earliest stages. The team next tested whether lipids mediate neurons' response to oxidative stress. The researchers bombarded cultured motor neurons from mice with a chemical that fires up the generation of superoxide molecules. The cells succumbed quickly. But in the presence of a molecule that blocks sphingolipid production, cells resisted the oxidative stress. Additional experiments revealed that blocking lipid synthesis also helped neurons survive an excess of glutamate, which pushes cells to churn out oxidizing free radicals. Together, the results suggest that motor neuron death in ALS requires a boost in lipid concentration. Diet might influence these lipid changes: A 2-year-old epidemiological study hints that a high-fat diet increases the risk of ALS. To further establish the link, says Mattson, scientists need to investigate whether ALS patients have higher blood concentrations of fatty acids. "It's an absolutely first-rate study," says neurologist Stan Appel of Baylor College of Medicine in Houston. Researchers have focused on developing antioxidant and anti-inflammatory drugs for ALS, says Appel: "What this says is that we've been ignoring something that is downstream. A lot of us are going to look carefully at [the role of lipids]." Drugs that quell sphingolipid production might give motor neurons footing to survive ALS's oxidative stress. --R. John Davenport R. G. Cutler, W. A. Pedersen, S. Camandola, J. D. Rothstein, M. P. Mattson, Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis. Ann. Neurol. 22 August 2002 [e-pub ahead of print]. [Abstract] [Full Text]

On the origin, evolution, and nature of programmed cell death: a timeline of four billion years.

Programmed cell death is a genetically regulated process of cell suicide that is central to the development, homeostasis and integrity of multicellular organisms. Conversely, the dysregulation of mechanisms controlling cell suicide plays a role in the pathogenesis of a wide range of diseases. While great progress has been achieved in the unveiling of the molecular mechanisms of programmed cell death, a new level of complexity, with important therapeutic implications, has begun to emerge, suggesting (i) that several different self-destruction pathways may exist and operate in parallel in our cells, and (ii) that molecular effectors of cell suicide may also perform other functions unrelated to cell death induction and crucial to cell survival. In this review, I will argue that this new level of complexity, implying that there may be no such thing as a 'bona fide' genetic death program in our cells, might be better understood when considered in an evolutionary context. And a new view of the regulated cell suicide pathways emerges when one attempts to ask the question of when and how they may have become selected during evolution, at the level of ancestral single-celled organisms.

Apoptosis and cancer: Strategies for integrating programmed cell death

Virtually all human cells are endowed with the capacity to commit suicide using an evolutionarily conserved mechanism that Involves activation of caspase-family cell death proteases. Caspase activation culminates in a cell death process known as “apoptosis.” The activation of these intracellular proteases is carefully controlled through a delicate balance of anti- and pro-death proteins, serving to precisely regulate cell life span. Defects in the natural death pathway promote tumorigenesis by prolonging cell life span and hence cell accumulation. Low-grade B-cell malignancies, particularly follicular lymphoma and chronic lymphocytic leukemia (CLL) represent quintessential examples of human neoplasms characterized primarily by a problem with cell death rather than cell cycle. Because the cell suicide pathway is also required for tumor eradication by the immune system, anticancer drugs, and irradiation, cancer-associated defects in the cellular apoptosis machinery also play an important role in treatment failures. Monoclonal antibody-based therapies may provide opportunities to either bypass defects in apoptosis pathways or to activate latent apoptotic programs in cancer cells, particularly in lymphoid malignancies where tissue-specific antigens can be exploited for cell-selective activation of apoptosis. Recent knowledge about apoptosis pathways is reviewed, and some examples of opportunities for therapeutic intervention are discussed.

Exposure to hydrogen peroxide induces cell death via apoptosis in primary cultured mouse hepatocytes.

To investigate whether direct oxidant damage induces hepatotoxicity via an apoptotic cell suicide pathway, we exposed primary cultured mouse hepatocytes to pro-oxidant hydrogen peroxide. We demonstrate that brief exposure to a concentration of hydrogen peroxide (3 mM) can induce hepatocyte cell death via apoptosis as shown by toxicity assays, specific DNA staining, and the appearance of DNA laddering on agarose gels. When hepatocytes were treated with N-acetylcysteine 15 min prior to hydrogen peroxide exposure, the cells were found to be protected from cytotoxicity and apoptosis. These results suggest that direct oxidative injury serves as a general trigger for apoptosis in the liver, and that other apoptotic stimuli, such as exposure to acetaminophen, also involve oxidative injury. Hydrogen peroxidase-induced apoptosis may serve as a valuable model for further studies of apoptosis in the liver.

Viral interference with apoptosis

Viruses have exploited a fascinating array of mechanisms to inhibit programed cell death. Different viruses tamper with cell suicide pathways by terminating cell death receptor signalling, mimicking cellular Bc1-2 functions, encoding protease inhibitors and other tactics. These stealth strategies are likely to be essential for the preservation of some viruses as it appears nearly impossible for a virus to enter a cell and set up housekeeping without setting off the alarm system that triggers activation of the cell death pathway. Thus, many viruses have developed strategies to subvert the cellular selfdestruct mechanisms, thereby providing suitable environments for long-term persistence, the establishment of latency or for progeny virus production. Investigation of these viral strategies has significantly advanced our knowledge of cellular death pathways and has impacted on our understanding of viral pathogenesis.

A Prion Protein Fragment Primes Type 1 Astrocytes to Proliferation Signals from Microglia

Gliosis is a hallmark of prion disease. A neurotoxic prion peptide (PrP106-126) induces astrocyte proliferation in the presence of microglia. This peptide also directly enhances microglial proliferation in culture. We have investigated this further to understand the method by which factors released by microglia and PrP106-126 work together to enhance astrocyte proliferation. PrP106-126 in the presence of microglia specifically enhanced type 1 astrocyte proliferation but not Type 2. Astrocytes that do not express the prion protein were more sensitive to oxidative stress and the toxicity of cytosine arabinoside. In the presence of cytosine arabinoside, PrP106-126 was toxic to pure astrocyte cultures. Using conditioned medium from microglia we have shown that PrPc-expressing astrocytes proliferate in response to factors released by microglia stimulated by granulocyte/macrophage colony-stimulating factor. This response is enhanced in the presence of PrP106-126. PrPc-deficient astrocytes do not show this response. These results suggest that astrocytes are primed by PrP106-126 to respond more to factors released by proliferating microglia. Astrocytes may proliferate in this system to escape entering the cell suicide pathway.

Multiple extracellular signals promote osteoblast survival and apoptosis.

Programed cell death (PCD) or apoptosis is a naturally occurring cell suicide pathway induced in a variety of cell types. In many cases, PCD apparently arises as a result of competition for limiting amounts of survival signals. In this study, we have investigated the potential role of growth factors (GF), cytokines, and osteotropic hormones on osteoblast survival in vitro. Our results indicate that in the absence of any of these factors, osteoblasts rapidly undergo PCD, as determined by cell morphology, mitochondrial function, and nuclei fragmentation. Osteoblast survival was promoted by insulin-like growth factor I (IGF-I), IGF-II, insulin, and basic fibroblast growth factor (bFGF). Platelet-derived growth factor had no effect on osteoblast survival, but this GF potentiated the survival-promoting effects of IGF-I, IGF-II, and insulin. A similar effect occurred when bFGF was added in combination with either of the IGFs or insulin. The effects of the IGFs were blocked by alphaIR-3, an antibody to the type I IGF receptor, whereas the effects of insulin were only partially blocked. This antibody blocked the potentiating effects of platelet-derived growth factor on IGF-I-mediated osteoblast survival, but only partially blocked those of bFGF. Although a 100% survival of osteoblasts was seen in the presence of 2% FCS, the highest level attained by any of the above GF combinations was approximately 75%. The monocyte-derived factor, tumor necrosis factor-alpha (TNF alpha) was the only agent that enhanced PCD in this study. These results suggest that osteoblast survival is promoted by those GFs sequestrated in bone matrix and that the type I, but not the type II, IGF receptor is involved in the response. Our data also indicate that other unidentified GFs or components of the extracellular matrix may be involved in promoting osteoblast survival and that TNF alpha may abrogate their effects in vivo. We propose that these GFs may be released from bone matrix during phases of bone resorption and promote osteoblast survival, thereby playing an important role in bone remodeling, and that PCD induced by TNF alpha may contribute to the bone loss in inflammatory bone disease.

Multiple Extracellular Signals Promote Osteoblast Survival and Apoptosis

Programed cell death (PCD) or apoptosis is a naturally occurring cell suicide pathway induced in a variety of cell types. In many cases, PCD apparently arises as a result of competition for limiting amounts of survival signals. In this study, we have investigated the potential role of growth factors (GF), cytokines, and osteotropic hormones on osteoblast survival in vitro. Our results indicate that in the absence of any of these factors, osteoblasts rapidly undergo PCD, as determined by cell morphology, mitochondrial function, and nuclei fragmentation. Osteoblast survival was promoted by insulin-like growth factor I (IGF-I), IGF-II, insulin, and basic fibroblast growth factor (bFGF). Platelet-derived growth factor had no effect on osteoblast survival, but this GF potentiated the survival-promoting effects of IGF-I, IGF-II, and insulin. A similar effect occurred when bFGF was added in combination with either of the IGFs or insulin. The effects of the IGFs were blocked by αIR-3, an antibody to the type I IGF receptor, whereas the effects of insulin were only partially blocked. This antibody blocked the potentiating effects of platelet-derived growth factor on IGF-I-mediated osteoblast survival, but only partially blocked those of bFGF. Although a 100% survival of osteoblasts was seen in the presence of 2% FCS, the highest level attained by any of the above GF combinations was ∼75%. The monocyte-derived factor, tumor necrosis factor-α (TNFα) was the only agent that enhanced PCD in this study. These results suggest that osteoblast survival is promoted by those GFs sequestrated in bone matrix and that the type I, but not the type II, IGF receptor is involved in the response. Our data also indicate that other unidentified GFs or components of the extracellular matrix may be involved in promoting osteoblast survival and that TNFα may abrogate their effects in vivo. We propose that these GFs may be released from bone matrix during phases of bone resorption and promote osteoblast survival, thereby playing an important role in bone remodeling, and that PCD induced by TNFα may contribute to the bone loss in inflammatory bone disease.

Ceramide and Cell Suicide Pathways

Ceramide and Cell Suicide Pathways

The Regulation of Neuronal Death during Insect Metamorphosis

occurs during normal development, as tissues form: for example, in the dorsal root ganglion of the chick spinal cord, only 60% of the nerve cells present before hatching survive to become part of the mature nervous system (Hamburger and LeviMontalcini 1949). Some nerve cells most likely die during development because they fail to find a synaptic target (Hollyday and Hamburger 1976). Cell death also maintains tissue mass in slowly proliferating adult tissues such as the liver, in which the production of new hepatic cells is balanced with cell loss (Beneditti et al. 1988). And without mechanisms for cell suicide, the striking morphological changes that accompany metamorphosis (of caterpillars or tadpoles, for example) would not be possible. Exciting new data indicate that this cell suicide pathway is evolutionarily ancient and highly conserved, because homologous molecules have the same suicide-