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PubMed1999

Programmed cell death in C. elegans.

Genetic screens in the hermaphrodite nematode worm Caenorhabditis elegans resulted in the identification of the basal conserved machinery of apoptosis, arguably the single most important finding for our understanding of cell death. The last two years have seen enormous progress in the elucidation of the molecular interactions that lie at the heart of this conserved machinery, along with major insights both into how cell death is activated in the worm and into the mechanism of recognition and engulfment of the cell corpses. In this review, I set out the current models of cell death regulation and execution in C. elegans, focussing in particular on the similarities between cell death in C. elegans and vertebrates. Finally, I attempt to highlight key areas for future progress in cell death research in C. elegans and explore additional ways in which the worm can be used to understand the regulation of cell death in mammals.

Animals↗
PubMed2003

Multiple mediators of plant programmed cell death: interplay of conserved cell death mechanisms and plant-specific regulators.

Programmed cell death (PCD) is a process aimed at the removal of redundant, misplaced, or damaged cells and it is essential to the development and maintenance of multicellular organisms. In contrast to the relatively well-described cell death pathway in animals, often referred to as apoptosis, mechanisms and regulation of plant PCD are still ill-defined. Several morphological and biochemical similarities between apoptosis and plant PCD have been described, including DNA laddering, caspase-like proteolytic activity, and cytochrome c release from mitochondria. Reactive oxygen species (ROS) have emerged as important signals in the activation of plant PCD. In addition, several plant hormones may exert their respective effects on plant PCD through the regulation of ROS accumulation. The possible plant PCD regulators discussed in this review are integrated in a model that combines plant-specific regulators with mechanisms functionally conserved between animals and plants.

Apoptosis↗
PubMed2002

Cell death may regulate visual functionality in the retina of adults of the dipteran Ceratitis capitata.

The white eye mutation in the medfly Ceratitis capitata, like the homologous mutation in Drosophila melanogaster, was shown to impair visual function. Light and electron microscopy, combined with the DNA-end labelling histochemistry (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) technique), were used to investigate whether programmed cell death may contribute to the morpho-functional differences between the retina of adults from the white eye and wild type strains. Several photoreceptor nuclei in mature white eye flies appeared smaller and showed intensely Toluidine Blue-stained chromatin masses. At the ultrastructural level, they showed different stages of degeneration, resembling apoptotic figures. Positive TUNEL labelling in the white eye retina indicates that apoptosis may be a candidate mechanism for retinal cell degeneration in adult flies, where visual functionality is altered, to achieve the proper cell number. Apoptosis also appears to occur in the wild type retina in early adult life during normal tissue development.

Aging↗
PubMed2004

[The role of apoptosis in the pathogenesis and treatment of neoplastic disorders of the hematopoietic system].

Defects in apoptotic cell-death regulation contribute to many disorders. Insufficient apoptosis leads to neoplastic and autoimmune disorders and chronic infections. Enhanced apoptosis is a cause of neurodegenerative disorder and complicates processes of ischemia. Genetic changes involving oncogenes and tumor suppressor genes contribute to the unregulated expansion of malignant cells. While some of these changes result in increased proliferation, others contribute to increasing cell numbers by inhibiting apoptosis. Because cytotoxic drugs or irradiation result in cell death by apoptosis, the genetic changes underlying malignancy often reduce the ability of these agents to destroy malignant cells. Knowledge of the molecular mechanisms of apoptosis provides insight into the causes of multiple pathologies where aberrant cell-death regulation occurs and provides new approaches to the treatment of human diseases.

Animals↗
PubMed2001

Steroid hormones regulate programmed cell death: a review.

Programmed cell death (PCD) is a physiologically active process which is essential for the proper functioning of any living tissue. The steroid hormones modulate the programme in the immunological and reproductive organs and tissues, such as the thymus gland, circulating thymocytes, uterus, vagina, testis, ovary and prostrate gland. The influence of steroid hormones on cell death is tissue specific; the same hormone can inhibit PCD in one tissue, and may promote PCD in another tissue. The roles of apoptosis and terminal differentiation have been examined, and the regulation of PCD by steroid hormones, assessed.

Animals↗
PubMed2000

Regulation of cell death by the Abl tyrosine kinase.

The c-abl proto-oncogene encodes a protein tyrosine kinase that is distributed in the nucleus and the cytoplasm of proliferating cells. In the nucleus, c-Abl activity is negatively regulated by the retinoblastoma protein (RB) and positively regulated by DNA damage signals. Activation of the c-Abl kinase by DNA damage requires the function of ATM, which regulates cell cycle checkpoint, DNA repair and apoptosis in response to DNA damage. Cells lacking c-Abl can activate cell cycle checkpoints and DNA repair, but show defects in apoptosis. The apoptosis defect of c-Abl deficient cells is correlated with a defect in the induction and activation of p73, which is a functional homologue of the p53 tumor suppressor protein and has pro-apoptotic activity. The inhibition of c-Abl by RB is consistent with RB's ability to block apoptosis; while the activation of c-Abl by ATM is consistent with ATM's ability to activate cell death. The oncogenic Bcr-Abl tyrosine kinase is a potent inhibitor of apoptosis, and it is retained exclusively in the cytoplasm of transformed cells. Interestingly, when Bcr-Abl is trapped inside of the nucleus through a combined disruption of its cytoplasmic retention and its nuclear export, this oncogenic Abl kinase induces apoptosis. Taken together, the current results support a role for the nuclear c-Abl tyrosine kinase in the regulation of apoptosis. Whether the cytoplasmic c-Abl kinase can actively inhibit apoptosis remains to be determined; however, a deliberate retention of c-Abl in the cytoplasm could potentially contribute to the attenuation of apoptosis response.

Apoptosis↗
PubMed1996

Apoptosis mediated by the TNF-related cytokine and receptor families.

T lymphocytes use several specialized mechanisms to induce apoptotic cell death. The tumor necrosis factor (TNF)-related family of membrane-anchored and secreted ligands represent a major mechanism regulating cell death and cell survival. These ligands also coordinate differentiation of tissue to defend against intracellular pathogens and regulate development of lymphoid tissue. Cellular responses are initiated by a corresponding family of specific receptors that includes two distinct TNFR (TNFR60 and TNFR80), Fas (CD95), CD40, p75NTF, and the recently identified lymphotoxin beta-receptor (LT beta R), among others. The MHC-encoded cytokines, TNF and LT alpha, form homomeric trimers, whereas LT beta assembles into heterotrimers with LT alpha, creating multimeric ligands with distinct receptor specificities. The signal transduction cascade is initiated by transmembrane aggregation (clustering) of receptor cytoplasmic domains induced by binding to their multivalent ligands. The TRAF family of Zn RING/finger proteins bind to TNFR80; CD40 and LT beta R are involved in induction NF kappa B and cell survival. TNFR60 and Fas interact with several distinct cytosolic proteins sharing the "death domain" homology region. TNF binding to TNFR60 activates a serine protein kinase activity and phosphoproteins are recruited to the receptor forming a multicomponent signaling complex. Thus, TNFRs use diverse sets of signaling molecules to initiate and regulate cell death and survival pathways.

Animals↗
PubMed2000

Exposure at the cell surface is required for gas3/PMP22 To regulate both cell death and cell spreading: implication for the Charcot-Marie-Tooth type 1A and Dejerine-Sottas diseases.

Gas3/PMP22 is a tetraspan membrane protein highly expressed in myelinating Schwann cells. Point mutations in the gas3/PMP22 gene account for the dominant inherited peripheral neuropathies Charcot-Marie-Tooth type 1A disease (CMT1A) and Dejerine-Sottas syndrome (DSS). Gas3/PMP22 can regulate apoptosis and cell spreading in cultured cells. Gas3/PMP22 point mutations, which are responsible for these diseases, are defective in this respect. In this report, we demonstrate that Gas3/PMP22-WT is exposed at the cell surface, while its point-mutated derivatives are intracellularly retained, colocalizing mainly with the endoplasmic reticulum (ER). The putative retrieval motif present in the carboxyl terminus of Gas3/PMP22 is not sufficient for the intracellular sequestration of its point-mutated forms. On the contrary, the introduction of a retrieval signal at the carboxyl terminus of Gas3/PMP22-WT leads to its intracellular accumulation, which is accompanied by a failure to trigger cell death as well as by changes in cell spreading. In addition, by substituting the Asn at position 41 required for N-glycosylation, we provide evidence that N-glycosylation is required for the full effect on cell spreading, but it is not necessary for triggering cell death. In conclusion, we suggest that the DSS and the CMT1A neuropathies derived from point mutations of Gas3/PMP22 might arise, at the molecular level, from a reduced exposure of Gas3/PMP22 at the cell surface, which is required to exert its biological functions.

3T3 Cells↗
PubMed2001

Hoxa3 and pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis.

The thymus and parathyroid glands in mice develop from a thymus/parathyroid primordium that forms from the endoderm of the third pharyngeal pouch. We investigated the molecular mechanisms that promote this unique process in which two distinct organs form from a single primordium, using mice mutant for Hoxa3 and Pax1. Thymic ectopia in Hoxa3(+/-)Pax1(-/-) compound mutants is due to delayed separation of the thymus/parathyroid primordium from the pharynx. The primordium is hypoplastic at its formation, and has increased levels of apoptosis. The developing third pouch in Hoxa3(+/-)Pax1(-/-) compound mutants initiates normal expression of the parathyroid-specific Gcm2 and thymus-specific Foxn1 genes. However, Gcm2 expression is reduced at E11.5 in Pax1(-/-) single mutants, and further reduced or absent in Hoxa3(+/-)Pax1(-/-) compound mutants. Subsequent to organ-specific differentiation from the shared primordium, both the parathyroids and thymus developed defects. Parathyroids in compound mutants were smaller at their formation, and absent at later stages. Parathyroids were also reduced in Pax1(-/-) mutants, revealing a new function for Pax1 in parathyroid organogenesis. Thymic hypoplasia at later fetal stages in compound mutants was associated with increased death and decreased proliferation of thymic epithelial cells. Our results suggest that a Hoxa3-Pax1 genetic pathway is required for both epithelial cell growth and differentiation throughout thymus and parathyroid organogenesis.

Animals↗
PubMed2005

From oogenesis through gastrulation: developmental regulation of apoptosis.

Apoptosis is a mechanism employed by multicellular organisms throughout development as a means of eliminating damaged or otherwise unwanted cells. From oogenesis through fertilization and gastrulation, organisms use an array of cell- and tissue-specific mechanisms to regulate the apoptotic program in response to stress or developmental cues. Since cell death regulation is tightly interwoven with cell cycle and checkpoint controls, and embryos of the fly, fish and frog exhibit unique embryonic cell cycle regulation, it is of great interest to understand how early embryos coordinate these cellular functions.

Animals↗
PubMed2006

Nitric oxide- and hydrogen peroxide-responsive gene regulation during cell death induction in tobacco.

Nitric oxide (NO) and hydrogen peroxide (H(2)O(2)) are regulatory molecules in various developmental processes and stress responses. Tobacco (Nicotiana tabacum) leaves exposed to moderate high light dramatically potentiated NO-mediated cell death in catalase-deficient (CAT1AS) but not in wild-type plants, providing genetic evidence for a partnership between NO and H(2)O(2) during the induction of programmed cell death. With this experimental model system, the specific impact on gene expression was characterized by either NO or H(2)O(2) alone or both molecules combined. By means of genome-wide cDNA-amplified fragment length polymorphism analysis, transcriptional changes were compared in high light-treated CAT1AS and wild-type leaves treated with or without the NO donor sodium nitroprusside. Differential gene expression was detected for 214 of the approximately 8,000 transcript fragments examined. For 108 fragments, sequence analysis revealed homology to genes with a role in signal transduction, defense response, hormone interplay, proteolysis, transport, and metabolism. Surprisingly, only 16 genes were specifically induced by the combined action of NO and H(2)O(2), whereas the majority were regulated by either of them alone. At least seven transcription factors were mutually up-regulated, indicating significant overlap between NO and H(2)O(2) signaling pathways. These results consolidate significant cross-talk between NO and H(2)O(2), provide new insight into the early transcriptional response of plants to increased NO and H(2)O(2) levels, and identify target genes of the combined action of NO and H(2)O(2) during the induction of plant cell death.

Base Sequence↗
PubMed2006

Proteome and transcriptome analysis of 5-fluoro-2'-deoxyuridine-induced cell death mechanisms.

5-Fluoro-2'-deoxyuridine (FUdR) inhibits thymidylate synthase. The inhibition of thymidylate synthase causes an imbalance of intracellular deoxyribonucleoside triphosphate (dNTP) pools which subsequently induced cell death. We have been investigated the molecular mechanisms of cell death in mouse mammary tumor FM3A cells, F28-7 strain and its mutant F28-7-A strain, after treated with FUdR. We have previously been reported that F28-7 strain induced DNA cleavage into chromosomal sized fragments and subsequently develop necrosis, but F28-7-A strain induced DNA cleavage into oligonucleosomal sized fragments and subsequently develop apoptosis after treated with FUdR. In this report, in order to understand the molecular mechanisms of regulate of two differential cell death necrosis and apoptosis, we identify cell death regulator by using proteome and transcriptome analysis. When compared with the proteome from F28-7 strain and F28-7-A strain, it was found that ten proteins were increased and six proteins were decreased in F28-7-A strain. Furthermore, transcriptome analysis shows that 127 genes were increased and 181 genes were decreased in F28-7-A strain. These differentially expressed proteins and genes were involved in various cellular processes such as cell cycle regulation, apoptosis, proliferation, and differentiation. These two techniques clarified numerous features in F28-7 strain and F28-7-A strain. Our results revealed that numerous features indicated the coordinated regulation of molecular networks from various aspects of necrosis or apoptosis at the proteome and transcriptome levels.

Animals↗
PubMed1997

Antisense RNA-regulated programmed cell death.

Eubacterial plasmids and chromosomes encode multiple killer genes belonging to the hok gene family. The plasmid-encoded killer genes mediate plasmid stabilization by killing plasmid-free cells. This review describes the genetics, molecular biology, and evolution of the hok gene family. The complicated antisense RNA-regulated control-loop that regulates posttranscriptional and postsegregational activation of killer mRNA translation in plasmid-free cells is described in detail. Nucleotide covariations in the mRNAs reveal metastable stem-loop structures that are formed at the mRNA 5' ends in the nascent transcripts. The metastable structures prevent translation and antisense RNA binding during transcription. Coupled nucleotide covariations provide evidence for a phylogenetically conserved mRNA folding pathway that involves sequential dynamic RNA rearrangements. Our analyses have elucidated an intricate mechanism by which translation of an antisense RNA-regulated mRNA can be conditionally activated. The complex phylogenetic relationships of the plasmid- and chromosome-encoded systems are also presented and discussed.

Apoptosis↗
PubMed2001

Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination.

Interferons (IFNs) and retinoids are potent tumor growth suppressors. We have shown earlier that the IFN-beta and all-trans retinoic acid combination, but not the single agents, induces death in several tumor cell lines. Employing a genetic approach we have recently identified several Genes associated with Retinoid-IFN induced Mortality (GRIM) that mediate the cell death effect of IFN/RA combination. One of the GRIMs, GRIM-12, was identical to human thioredoxin reductase (TR), an enzyme that controls intracellular redox state. To define the participants of TR mediated death pathway we have examined the role of thioredoxin (Trx), its downstream substrate, and its influence on IFN/RA-induced death regulation. Inhibition of the thioredoxin expression by antisense RNA suppressed cell death. Similarly, a mutant Trx1 lacking the critical cysteine residues blocked cell death. In contrast, overexpression of wildtype thioredoxin augmented cell death. This effect of Trx1 was in part due to its ability to augment cell death via caspase-8. The redox inactive Trx1 mutant inhibits the cell death induced by caspase-8 but not caspase-3. These studies identify a novel mechanism of cell death regulation by IFN/RA combination involving redox enzymes.

Antineoplastic Agents↗
PubMed1995

Lack of correlation between c-myc expression and programmed or experimentally-induced cell death during chick limb development.

The protooncogene c-myc positively regulates cell death in most in vitro cell model systems under conditions of restricted proliferation, and it has been proposed that cell death is a physiological function of c-myc. To investigate possible changes in c-myc expression concomitant with programmed cell death, we have analyzed c-myc mRNA expression during chick limb development. Expression of c-myc was high in the premuscular masses at earlier stages and in the chondrogenic condensations at later stages of limb development, as demonstrated by in situ mRNA hybridization in sections and whole-mount. However, we did not detect c-myc expression in specific limb areas where massive apoptosis was occurring. Furthermore, when the apical ridge was removed from stage 20 wing buds, there was no increase in the expression of c-myc in the subridge mesoderm, despite the extensive cell death induced by this surgical manipulation. Therefore, our results show no correlation between elevated c-myc expression and either programmed or experimentally-induced apoptosis in the developing limb. These results argue against a role of c-myc in cell death occurring in vivo.

Animals↗
PubMed2001

The disease resistance signaling components EDS1 and PAD4 are essential regulators of the cell death pathway controlled by LSD1 in Arabidopsis.

Specific recognition of pathogens is mediated by plant disease resistance (R) genes and translated into a successful defense response. The extent of associated hypersensitive cell death varies from none to an area encompassing cells surrounding an infection site, depending on the R gene activated. We constructed double mutants in Arabidopsis between positive regulators of R function and a negative regulator of cell death, LSD1, to address whether genes required for normal R function also regulate the runaway cell death observed in lsd1 mutants. We report here that EDS1 and PAD4, two signaling genes that mediate some but not all R responses, also are required for runaway cell death in the lsd1 mutant. Importantly, this novel function of EDS1 and PAD4 is operative when runaway cell death in lsd1 is initiated through an R gene that does not require EDS1 or PAD4 for disease resistance. NDR1, another component of R signaling, also contributes to the control of plant cell death. The roles of EDS1 and PAD4 in regulating lsd1 runaway cell death are related to the interpretation of reactive oxygen intermediate-derived signals at infection sites. We further demonstrate that the fate of superoxide at infection sites is different from that observed at the leading margins of runaway cell death lesions in lsd1 mutants.

Arabidopsis↗
PubMed1996

Apoptosis: molecular regulation of cell death.

The field of apoptosis is unusual in several respects. Firstly, its general importance has been widely recognised only in the past few years and its surprising significance is still being evaluated in a number of areas of biology. Secondly, although apoptosis is now accepted as a critical element in the repertoire of potential cellular responses, the picture of the intra-cellular processes involved is probably still incomplete, not just in its details, but also in the basic outline of the process as a whole. It is therefore a very interesting and active area at present and is likely to progress rapidly in the next two or three years. This review emphasises recent work on the molecular mechanisms of apoptosis and, in particular, on the intracellular interactions which control this process. This latter area is of crucial importance since dysfunction of the normal control machinery is likely to have serious pathological consequences, probably including oncogenesis, autoimmunity and degenerative disease. The genetic analysis of programmed cell death during the development of the nematode Caenorhabditis elegans has proved very useful in identifying important events in the cell death programme. Recently defined genetic connections between C. elegans cell death and mammalian apoptosis have emphasised the value of this system as a model for cell death in mammalian cells, which, inevitably, is more complex. The signals inducing apoptosis are very varied and the same signals can induce differentiation and proliferation in other situations. However, some pathways appear to be of particular significance in the control of cell death; recent analysis of the apoptosis induced through the cell-surface Fas receptor has been especially important for immunology. Two gene families are dealt with in particular detail because of their likely importance in apoptosis control. These are, first, the genes encoding the interleukin-1 beta-converting enzyme family of cysteine proteases and, second, those related to the proto-oncogene bcl-2. Both of these families are homologous to cell death genes in C. elegans. In mammalian cells the number of members of both families which have been identified is growing rapidly and considerable effort is being directed towards establishing the roles played by each member and the ways in which they interact to regulate apoptosis. Other genes with established roles in the regulation of proliferation and differentiation are also important in controlling apoptosis. Several of these are known proto-oncogenes, e.g. c-myc, or tumour suppressors, e.g. p53, an observation which is consistent with the importance of defective apoptosis in the development of cancer. Viral manipulation of the apoptosis of host cells frequently involves interactions with these cellular proteins. Finally, the biochemistry of the closely controlled cellular self-destruction which ensues when the apoptosis programme has been engaged is also very important. The biochemical changes involved in inducing phagocytosis of the apoptotic cell, for example, allow the process to be neatly integrated within the tissues, under physiological conditions. Molecular defects in this area too may have important pathological consequences.

Amino Acid Sequence↗