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Results for “programmed cell death”

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PubMed1994

From AIDS to parasite infection: pathogen-mediated subversion of programmed cell death as a mechanism for immune dysregulation.

Premature cell death can result either from cell injury or degeneration, leading to necrosis, or from the activation of a physiological cell-suicide process, termed programmed cell death or apoptosis, that is regulated by intercellular signalling. This process plays an essential role in the selection of developing lymphocytes, and is also involved in the function of the mature adaptative immune system. A growing number of experimental findings during the last 4 years has provided support to our hypothesis that inappropriate HIV-mediated dysregulation of programmed T-cell death is relevant to AIDS pathogenesis. A series of recent experimental results also supports the general concept that the persistence and pathogenesis of several infectious pathogens, ranging from retroviruses to parasites, may be related to their capacity to dysregulate programmed cell death in various cell populations including lymphocytes. Subversion by pathogens of the physiological control of programmed cell death provides a paradigm for the pathogenesis of a wide range of infectious diseases that involve immune dysregulation and suggests therapeutic potential for the in vivo modulation of cell signalling.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Free radicals and reactive oxygen species in programmed cell death.

Oxidative stress, originating from reactive oxygen species and free radicals provides a constant challenge to eukaryotic cell survival. While implicated in a number of degenerative diseases, some associated with aging and with aging itself, the manner and extent to which oxidative stress contributes to the initiation or implementation of programmed-cell death is problematic. If oxidative stress is an important modulator of programmed-cell death, any ability intentionally to augment or inhibit it might ameliorate diseases in which the process is abnormally underactive or overactive.

Animals↗
PubMed2005

Characterization of a serine protease-mediated cell death program activated in human leukemia cells.

Tightly controlled proteolysis is a defining feature of apoptosis and caspases are critical in this regard. Significant roles for non-caspase proteases in cell death have been highlighted. Staurosporine causes a rapid induction of apoptosis in virtually all mammalian cell types. Numerous studies demonstrate that staurosporine can activate cell death under caspase-inhibiting circumstances. The aim of this study was to investigate the proteolytic mechanisms responsible for cell death under these conditions. To that end, we show that inhibitors of serine proteases can delay cell death in one such system. Furthermore, through profiling of proteolytic activation, we demonstrate, for the first time, that staurosporine activates a chymotrypsin-like serine protease-dependent cell death in HL-60 cells independently, but in parallel with the caspase controlled systems. Features of the serine protease-mediated system include cell shrinkage and apoptotic morphology, regulation of caspase-3, altered nuclear morphology, generation of an endonuclease and DNA degradation. We also demonstrate a staurosporine-induced activation of a putative 16 kDa chymotrypsin-like protein during apoptosis.

Apoptosis↗
PubMed2005

[Programmed cell death: history and future of a concept].

Cell death was observed and understood since the 19th century, but there was no experimental examination until the mid-20th century. Beginning in the 1960's, several laboratories demonstrated that cell death was biologically controlled (programmed) and that the morphology was common and not readily explained (apoptosis). By 1990 the genetic basis of programmed cell death had been established and the first components of the cell death machinery (caspase 3, bcl-2 and Fas) had been identified, sequenced, and recognized as highly conserved in evolution. The rapid development of the field has given us substantial understanding of how cell death is achieved. However, capitalizing on our knowledge for therapeutic purposes requires us to learn much more about how a cell commits to death, as well as recognizing that apoptosis may be the most common and efficient means of death, but that there are alternative pathways that can result in cell death even when the conventional pathway is blocked. Interestingly enough, many of the arguments and missteps in the history of the field were anticipated by Claude Bernard, and his warnings and recommendations remain valid today.

Animals↗
PubMed1996

[Modulation of bcl-2 antisense RNA on programmed cell death of leukemic cell line].

OBJECTIVE: To investigate modulation of decrease of intrinsic bcl-2 protein levels on programmed cell death of leukemia cells. METHOD: Gene transfection procedure was applied to observe the effect of antisense RNA-mediated suppression of bcl-2 gene expression on programmed cell death of human T-lymphocytic leukemia cell line CEM. RESULTS: Temporary expression of antisense bcl-2 gene could effectively reduce levels of intrinsic bcl-2 protein of CEM cells and render it more sensitive to etoposide-induced cytotoxicity. Moreover, a great deal of apoptotic bodies and ladder DNA was always produced during etoposide-mediated killing of CEM and when CEM expressing bcl-2 antisense RNA served as target cells in particular, the amount of ladder DNA increased to around 40%. CONCLUSION: Programmed cell death is one of the mechanisms by which etoposide kills leukemic cells and is modulated by cellular intrinsic bcl-2 protein.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Induction of multiple programmed cell death pathways by IFN-beta in human non-small-cell lung cancer cell lines.

Tissue transglutaminase (tTG) and keratinocyte transglutaminase (kTG), as well as the cross-linked envelopes (CLE) that they form, have been associated with squamous differentiation and programmed cell death in epithelial cells. When interferon-beta (IFN-beta) was used to stimulate differentiation and programmed cell death in the human lung cancer cell lines NCI-H596 and NCI-H226, the cells underwent a decrease in cellular density. In NCI-H596 IFN-beta caused an increase in kTG activity and DNA fragmentation in the lower density cells, which were significantly slower growing than control cells. However, in the higher density cells, which were only slightly slower growing than control cells, IFN-beta caused an increase in tTG activity and CLE competence. Dual-parameter flow cytometry demonstrated that IFN-beta-induced squamous differentiation preceded programmed cell death. Treatment of NCI-H596 cells with monodansylcadaverine, a transglutaminase inhibitor, prevented the increase in CLE competence, but did not inhibit DNA fragmentation. These results suggest that IFN-beta can induce NCI-H596 cells to enter multiple cell death pathways and that these pathways are not only differentiation related, but may also be growth driven.

Apoptosis↗
PubMed1991

Immunocytochemical demonstration of tissue transglutaminase indicative of programmed cell death (apoptosis) in hormone sensitive mammary tumours.

Tissue transglutaminase (TG) positive tumour cells in MXT mouse mammary cancer were localized by immunohistochemistry. The number of TG-positive tumour cells increased after treatment with analogs of luteinizing hormone-releasing hormone (LH-RH) and somatostatin, which inhibit tumour growth by the enhancement of apoptosis (programmed cell death). TG positivity has been previously reported to be closely linked with apoptosis. In this study, the increase in the number of TG positive tumour cells after hormonal treatment was well correlated with the augmented apoptotic index, i.e. the ratio of tumourous glandular structures which contained tumour cells showing the signs of programmed cell death. TG-positive tumour cells are, therefore, believed to be undergoing programmed cell death.

Amino Acid Sequence↗
PubMed1998

Programmed cell death in the development of the mouse external auditory canal.

Programmed cell death (PCD) is an essential event for development. The purpose of this work was to ascertain how PCD, in vivo designated apoptosis, is involved in the development of the external auditory canal. We performed a time sequence study of the distribution of apoptosis during the development of external auditory canal (EAC) of the mouse. ICR mice ranging in age from embryonic day 11.5 (E11.5) to 12 days after birth (DAB) were used in the present study. A part of each head including both ears was removed and was processed according to its purpose. Light and electron microscopy for morphological studies and TUNEL method (Gavrieli et al. [1992] J Cell Biol., 119:493-501) for histochemical studies were used. On E11.5, distinct TUNEL-positive staining occurred in the branchial arch. Between E15.5 and 1DAB, TUNEL-positive cells were observed throughout the EAC and the number of these cells decreased with age. On E15.5 and E16.5, numerous TUNEL-positive cells were observed in a cavity remained in the epithelial plate. Transmission electron microscopy revealed that these cells had the features of apoptosis. From 3-12 DAB, no apoptosis was observed in the EAC except for the terminal differentiation of the skin of the EAC. Apoptosis was not observed during recanalization of the EAC, but occurred during the formation of the epithelial plate. The investigation established that PCD is involved in the formation of the epithelial plate, whereas only cornification of the epithelium of the EAC is associated with recanalization.

Animals↗
PubMed2000

Membrane asymmetry and DNA degradation: functionally distinct determinants of neuronal programmed cell death.

The ability to elucidate the molecular mechanisms that modulate programmed cell death (PCD) may provide the crucial clues to unravel the cellular basis of neurodegenerative disorders. Employing both a novel assay to follow serially PCD in individual living neurons and the neuroprotective agent lubeluzole as an investigative tool, we examined the development of nitric oxide (NO)-induced PCD over time through the reversible annexin V labelling of membrane phosphatidylserine (PS) exposure and the electron microscopy of genomic DNA in primary rat hippocampal neurons. Exposure to the NO generators SNP (300 microM) or NOC-9 (300 microM) alone increased annexin V-positive neurons in the population from 7% +/- 4% in untreated cultures to 13% +/- 4% at 1 hr and to 61% +/- 5% at 24 hr. Administration of a neuroprotective concentration of lubeluzole (750 nM) at the time of NO exposure initially prevented the exposure of PS residues, but consistently maintained DNA integrity over a 24 hr period. During posttreatment paradigms of lubeluzole (750 nM) at 2, 4, and 6 hr following NO exposure, progression of membrane PS inversion was reversed and subsequently suppressed over a 24 hr course. Our work illustrates that neuronal PCD is composed of at least two physiologically distinct and separate pathways that consist of the externalization of membrane PS residues and the independent maintenance of genomic DNA integrity. In addition, neuronal injury is fluid and reversible in nature, suggesting a "window of opportunity" for the repair and reversal of neurons yet to be committed to PCD.

Animals↗
PubMed2001

Ricinosomes: an organelle for developmentally regulated programmed cell death in senescing plant tissues.

This review describes aspects of programmed cell death (PCD). Present research maps the enzymes involved and explores the signal transduction pathways involved in their synthesis. A special organelle (the ricinosome) has been discovered in the senescing endosperm of germinating castor beans (Ricinus communis) that develops at the beginning of PCD and delivers large amounts of a papain-type cysteine endopeptidase (CysEP) in the final stages of cellular disintegration. Castor beans store oil and proteins in a living endosperm surrounding the cotyledons. These stores are mobilized during germination and transferred into the cotyledons. PCD is initiated after this transfer is complete. The CysEP is synthesized in the lumen of the endoplasmic reticulum (ER) where it is retained by its C-terminal KDEL peptide as a rather inactive pro-enzyme. Large number of ricinosomes bud from the ER at the same time as the nuclear DNA is characteristically fragmented during PCD. The mitochondria, glyoxysomes and ribosomes are degraded in autophagic vacuoles, while the endopeptidase is activated by removal of the propeptide and the KDEL tail and enters the cytosol. The endosperm dries and detaches from the cotyledons. A homologous KDEL-tailed cysteine endopeptidase has been found in several senescing tissues; it has been localized in ricinosomes of withering day-lily petals and dying seed coats. Three genes for a KDEL-tailed cysteine endopeptidase have been identified in Arabidopsis. One is expressed in senescing ovules, the second in the vascular vessels and the third in maturing siliques. These genes open the way to exploring PCD in plants.

Apoptosis↗
PubMed1995

Quantification of apoptosis (programmed cell death) in mammalian testis by DNA-fragmentation ELISA.

Apoptosis (programmed cell death) could contribute to fluctuations in sperm production and involution of testis in dependence on seasonal, genetic, environmental or individual factors. Investigations of such factors require a reliable quantitative examination of apoptotic processes. Therefore, a standardized procedure was developed for quantification of apoptosis in samples of testicular parenchyma in bull. This test is based on a highly sensitive DNA-fragmentation ELISA which was used originally for somatic cells in culture. Aliquots of testicular parenchyma were minced and homogenized by freezing/thawing and subsequent sonification at 4 degrees C. In comparison, aliquots were lysed in original buffer from the cell death detection ELISA-kit. Nucleosomes from the cell cytoplasm were obtained in supernatant of homogenate or lysate after centrifugation. The absorbance was linear over the range of sample concentrations from 5 to 20 microg testis equivalent/100 microl solution. Therefore, samples were standardized to a final concentration of 10 microg testis equivalent/100 microl. The recorded values were expressed in units per mg tissue (U/mg). The method was used to study testicular apoptotic processes in the guinea pig and roe deer. The results showed that apoptosis can be detected in testicular homogenate prepared from 0.01 mg testis parenchyma within 24 h after recovery of testes without significant variations. Detectable apoptosis levels showed differences among sexually active guinea pig (7.08 +/- 1.95 U/mg), roe deer (16.32 +/- 3.45 U/mg), and cattle (29.0 +/- 7.1 U/mg). This species-specificity suggests different cross reactivity of the monoclonal antibody used in the ELISA. A significantly higher amount of testicular apoptosis was detected in a population of guinea pigs with increased inbreeding coefficients (f = 0.785 - 0.998) than in outbred animals (11.41 +/- 3.50 U/mg and 7.08 +/- 1.95 U/mg, respectively). The inverse relationship of testicular apoptosis and proliferation in these two populations was significant (r = -0.531; P < 0.05). In conclusion, the relative simplicity and high sensitivity of this nonradioactive method provides a useful approach to investigate spermatogenesis under different conditions. Results in the guinea pig showed that apoptosis plays an important role in the regulation of gonadal efficiency.

Journal Article↗
PubMed2006

Non-self recognition and programmed cell death in filamentous fungi.

Non-self recognition resulting in programmed cell death is a ubiquitous phenomenon in filamentous ascomycete fungi and is termed heterokaryon incompatibility (HI). Recent analyses show that genes containing predicted HET domains are often involved in HI; however, the function of the HET domain is unknown. Autophagy is induced as a consequence of HI, whereas the presence of a predicted transcription factor, VIB-1, is required for HI. Morphological features associated with apoptosis in filamentous fungi are induced by various stresses and drugs, and also during HI. Future analyses will reveal whether common or different genetic mechanisms trigger death by non-self recognition and death by various environmental onslaughts.

Apoptosis↗
PubMed2004

Programmed cell death in trypanosomatids: a way to maximize their biological fitness?

Programmed cell death (PCD) is a biochemical process that plays an essential role in the development of multicellular organisms. However, accumulating evidence indicates that PCD is also present in single-celled eukaryotes. Thus, trypanosomatids might be endowed with a PCD mechanism that is derived from ancestral death machinery. PCD in trypanosomatids could be a process without a defined function, inherited through eukaryotic cell evolution, which might be triggered in response to diverse stimuli and stress conditions. However, recent observations suggest that PCD might be used by trypanosomatids to maximize their biological fitness. Therefore, PCD could represent a potential pharmacological target for protozoan control.

Animals↗
PubMed1997

Expression of Bax and bcl-2 proteins, regulators of programmed cell death, in human brain tumors.

Expression of Bcl-2, a programmed cell death (PCD)-suppressing molecule, and Bax, the Bcl-2 related PCD-accelerating protein was investigated in varied human brain tumors. Thirty-six cases of human brain tumors comprising 4 astrocytomas, 3 anaplastic astrocytomas, 4 glioblastomas multiforme, 5 medulloblastomas, 1 ependymoma, 2 choroid plexus papilloma, 1 ganglioglioma, 1 central neurocytoma, 4 meningotheliomatous meningiomas, 3 transitional meningiomas, 4 fibroblastic meningiomas, 3 acoustic neurinomas and 1 craniopharyngioma were analyzed for the localization of Bax and Bcl-2 proteins. No relationship between the degree of the histological malignancy and the presence of Bax or Bcl-2 proteins was found in varied human brain tumors. However, it is suggested that reduced expression of Bax protein is necessary for the malignant transformation and progression of the brain tumors, since no histologically malignant brain tumors with positive Bax protein were present. Our findings indicate that the expression pattern of Bax and Bcl-2 may reflect histogenetic difference of each type of brain tumors.

Adolescent↗
PubMed1992

Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.

Programmed cell death (PCD) plays a key role in developmental biology and in maintenance of the steady state in continuously renewing tissues. Currently, its existence is inferred mainly from gel electrophoresis of a pooled DNA extract as PCD was shown to be associated with DNA fragmentation. Based on this observation, we describe here the development of a method for the in situ visualization of PCD at the single-cell level, while preserving tissue architecture. Conventional histological sections, pretreated with protease, were nick end labeled with biotinylated poly dU, introduced by terminal deoxy-transferase, and then stained using avidin-conjugated peroxidase. The reaction is specific, only nuclei located at positions where PCD is expected are stained. The initial screening includes: small and large intestine, epidermis, lymphoid tissues, ovary, and other organs. A detailed analysis revealed that the process is initiated at the nuclear periphery, it is relatively short (1-3 h from initiation to cell elimination) and that PCD appears in tissues in clusters. The extent of tissue-PCD revealed by this method is considerably greater than apoptosis detected by nuclear morphology, and thus opens the way for a variety of studies.

Animals↗
PubMed1995

The head involution defective gene of Drosophila melanogaster functions in programmed cell death.

Deletions of chromosomal region, 75C1,2 block virtually all programmed cell death (PCD) in the Drosophila embryo. We have identified a gene previously in this interval, reaper (rpr), which encodes an important regulator of PCD. Here we report the isolation of a second gene in this region, head involution defective (hid), which plays a similar role in PCD. hid mutant embryos have decreased levels of cell death and contain extra cells in the head. We have cloned the hid gene and find that its expression is sufficient to induce PCD in cell death defective mutants. The hid gene appears to encode a novel 410-amino-acid protein, and its mRNA is expressed in regions of the embryo where cell death occurs. Ectopic expression of hid in the Drosophila retina results in eye ablation. This phenotype can be suppressed completely by expression of the anti-apoptotic p35 protein from baculovirus, indicating that p35 may act genetically downstream from hid.

Alleles↗
PubMedDate not supplied

[Aspects of cellular biology of the bacterial stationary phase: programmed cell death and regulation by guanosine tetraphosphate].

The paper discusses (1) programmed cell death, the phenomenon typical of the stationary phase of bacteria occurring under unfavorable conditions, (2) its pleiotropic regulation by guanosine tetraphosphate, and (3) the conception of "addiction module," a specific genetic system responsible for the cell choice between survival and death under unfavorable conditions. The shortcomings of the proposed interpretation of the problem at hand are considered and the necessity of their further investigation is substantiated.

Apoptosis↗