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691
Oxygen stress: a regulator of apoptosis in yeast
- J. Cell
, 1999
"... Abstract. Oxygen radicals are important components of metazoan apoptosis. We have found that apoptosis can be induced in the yeast Saccharomyces cerevisiae by depletion of glutathione or by low external doses of H 2O 2. Cycloheximide prevents apoptotic death revealing active participation of the cel ..."
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Cited by 126 (9 self)
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Abstract. Oxygen radicals are important components of metazoan apoptosis. We have found that apoptosis can be induced in the yeast Saccharomyces cerevisiae by depletion of glutathione or by low external doses of H 2O 2. Cycloheximide prevents apoptotic death revealing active participation of the cell. Yeast can also be triggered into apoptosis by a mutation in CDC48 or by expression of mammalian bax. In both cases, we show oxygen radicals to accumulate in the cell, whereas radical depletion or hypoxia prevents apoptosis. These results suggest that the generation of oxygen radicals is a key event in the ancestral apoptotic pathway and offer an explanation for the mechanism of bax-induced apoptosis in the absence of any established apoptotic gene in yeast.
A yeast mutant showing diagnostic markers of early and late apoptosis
- J. Cell
, 1997
"... Abstract. A Saccharomyces cerevisiae mutant in cell division cycle gene CDC48 shows typical markers of apoptosis: membrane staining with annexin V, indicating an exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane; intense staining, using the terminal deoxynucleotidyl trans ..."
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Cited by 90 (10 self)
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Abstract. A Saccharomyces cerevisiae mutant in cell division cycle gene CDC48 shows typical markers of apoptosis: membrane staining with annexin V, indicating an exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane; intense staining, using the terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling method, indicating DNA fragmentation; and chromatin condensation and fragmentation. The coordinate occurrence of these events at different locations in the cell, which have no obvious connection except their relation to apoptosis, implies the presence of the molecular machinery performing the basic steps of apoptosis already in yeast. Saccharomyces cerevisiae may prove a suitable model to trace the roots of apoptosis. Apoptosis is a form of programmed cell death with an important role in development and homeostasis of metazoan organisms. Apoptosis allows the rapid removal of unwanted or damaged cells that could otherwise inflame the surrounding cells with their cytoplasmic contents. In contrast, during necrosis, a form of cell death that results from overwhelming cellular injury, cells lyse and release cytoplasmic material. The apoptotic program is switched on in irreparably damaged or potentially dangerous cells such as self-reactive lymphocytes or cells that have been infected by viruses. Furthermore, it is involved in tumor suppression and in a wide range of diseases such as AIDS, neurodegenerative processes, and ischemic stroke
Porcine reproductive and respiratory syndrome virus - a persistent infection
- Proc 2nd Int Symp on PRRS
, 1995
"... Like other arteriviruses, porcine reproductive and respiratory syndrome virus (PRRSV) is shed in semen, a feature that is critical for the venereal transmission of this group of viruses. In spite of its epidemiological importance, little is known of the association of PRRSV or other arteriviruses wi ..."
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Cited by 62 (14 self)
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Like other arteriviruses, porcine reproductive and respiratory syndrome virus (PRRSV) is shed in semen, a feature that is critical for the venereal transmission of this group of viruses. In spite of its epidemiological importance, little is known of the association of PRRSV or other arteriviruses with gonadal tissues. We experimentally infected a group of boars with PRRSV 12068-96, a virulent field strain. By combined use of in situ hybridization and immunohistochemistry, we detected infection by PRRSV in the testes of these boars. The PRRSV testicular replication in testis centers on two types of cells: (i) epithelial germ cells of the seminiferous tubules, primarily spermatids and spermatocytes, and (ii) macrophages, which are located in the interstitium of the testis. Histopathologically, hypospermatogenesis, formation of multinucleated giant cells (MGCs), and abundant germ cell depletion and death were observed. We obtained evidence that such germ cell death occurs by apoptosis, as determined by a characteristic histologic pattern and evidence of massive DNA fragmentation detected in situ (TUNEL [terminal deoxynucleotidyltransferase-mediated digoxigenin-UTP nick end labeling] assay). Simultaneously with these testicular alterations, we observed that there is a significant increase in the number of immature sperm cells (mainly MGCs, spermatids, and spermatocytes) in the ejaculates of the PRRSV-inoculated boars and that these cells are infected with PRRSV. Our results indicate that PRRSV may infect target cells other than macrophages, that these infected cells can be primarily responsible for the
Increased production of tumor necrosis factoralpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J.Neurosci
, 2000
"... Although glial cells in the optic nerve head undergo a reactivation process in glaucoma, the role of glial cells during glaucomatous neurodegeneration of retinal ganglion cells is unknown. Using a coculture system in which retinal ganglion cells and glial cells are grown on different layers but shar ..."
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Cited by 54 (6 self)
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Although glial cells in the optic nerve head undergo a reactivation process in glaucoma, the role of glial cells during glaucomatous neurodegeneration of retinal ganglion cells is unknown. Using a coculture system in which retinal ganglion cells and glial cells are grown on different layers but share the same culture medium, we studied the influences of glial cells on survival of retinal ganglion cells after exposure to different stress conditions typified by simulated ischemia and elevated hydrostatic pressure. After the exposure to these stressors, we observed that glial cells secreted tumor necrosis factor- � (TNF-�) as well as other noxious agents such as nitric oxide into the coculture media and facilitated the apoptotic death of retinal ganglion cells as assessed by morphology, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and caspase activity. The glial origin of these noxious effects was confirmed by passive transfer experiments.
Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation
- J Cell Biol
, 1999
"... Abstract. The LAMC1 gene coding for the laminin �1 subunit was targeted by homologous recombination in mouse embryonic stem cells. Mice heterozygous for the mutation had a normal phenotype and were fertile, whereas homozygous mutant embryos did not survive beyond day 5.5 post coitum. These embryos l ..."
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Cited by 49 (3 self)
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Abstract. The LAMC1 gene coding for the laminin �1 subunit was targeted by homologous recombination in mouse embryonic stem cells. Mice heterozygous for the mutation had a normal phenotype and were fertile, whereas homozygous mutant embryos did not survive beyond day 5.5 post coitum. These embryos lacked basement membranes and although the blastocysts had expanded, primitive endoderm cells remained in the inner cell mass, and the parietal yolk sac did not develop. Cultured embryonic stem cells appeared normal after targeting both LAMC1 genes, but the embryoid bodies derived from them also lacked basement membranes, having disorganized extracellular deposits of the basement membrane proteins collagen IV and perlecan, and the cells failed to differentiate into stable myotubes. Secretion
Alphavirus-induced apoptosis in mouse brains correlates with neurovirulence
- J Virol
, 1996
"... correlates with neurovirulence. ..."
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Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance
- J. Cell
, 1999
"... Abstract. The role of transmembrane 4 superfamily (TM4SF) proteins during muscle cell fusion has not been investigated previously. Here we show that the appearance of TM4SF protein, CD9, and the formation of CD9–�1 integrin complexes were both regulated in coordination with murine C2C12 myoblast cel ..."
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Cited by 47 (3 self)
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Abstract. The role of transmembrane 4 superfamily (TM4SF) proteins during muscle cell fusion has not been investigated previously. Here we show that the appearance of TM4SF protein, CD9, and the formation of CD9–�1 integrin complexes were both regulated in coordination with murine C2C12 myoblast cell differentiation. Also, anti-CD9 and anti-CD81 monoclonal antibodies substantially inhibited and delayed conversion of C2C12 cells to elongated myotubes, without affecting muscle-specific protein expression. Studies of the human myoblast-derived RD sarcoma cell line further demonstrated that TM4SF proteins have a role during muscle cell fusion. Ectopic expression of CD9 caused a four- to eightfold increase in RD cell syncytia formation, whereas anti-CD9 and anti-CD81 antibodies markedly delayed RD syncytia formation. Finally, anti-CD9 and anti-CD81 monoclonal antibodies triggered apoptotic degeneration of C2C12 cell myotubes after they were formed. In summary, TM4SF proteins such as CD9 and CD81 appear to promote muscle cell fusion and support myotube maintenance.
In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintainance of differentiation, and regulation of programmed cell death
- J. Cell Biol
, 1995
"... Abstract. A model system is described for defining the physiologic functions of mammalian cadherins in vivo. 129/Sv embryonic stem (ES) cells, stably transfected with a dominant negative N-cadherin mutant (NCADA) under the control of a promoter that only functions in postmitotic enterocytes during t ..."
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Cited by 43 (2 self)
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Abstract. A model system is described for defining the physiologic functions of mammalian cadherins in vivo. 129/Sv embryonic stem (ES) cells, stably transfected with a dominant negative N-cadherin mutant (NCADA) under the control of a promoter that only functions in postmitotic enterocytes during their rapid, orderly, and continuous migration up small intestinal villi, were introduced into normal C57B1/6 (B6) blastocysts. In adult B6~129/Sv chimeric mice, each villus receives the cellular output of several surrounding monoclonal crypts. A polyclonal villus located at the boundary of 129/Sv- and B6-derived intestinal epithelium contains vertical coherent bands of NCADAproducing enterocytes plus adjacent bands of normal B6-derived enterocytes. A comparison of the biological
Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy
- J Exp Med
, 2001
"... The mechanism of CD4 � T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1–infected patients naive to antiretroviral drug ..."
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Cited by 41 (8 self)
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The mechanism of CD4 � T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1–infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death. In CD4 � T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls. In CD8 � T cells, the mean proliferation rate was 7.7-fold higher in HIV-1 infection, but the mean death rate was not significantly increased. Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy. The lymphocyte proliferation and death rates in both CD4 � and CD8 � cell populations were substantially reduced by 5–11 weeks and nearly normal by one year. Taken together, these new findings strongly indicate that CD4 � lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production. Key words: deuterated glucose • longitudinal study • mathematical model • apoptosis • mechanisms of CD4 � T cell depletion
Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation
- J. Immunol
, 1998
"... Infection by Mycobacterium tuberculosis (MTB) induces human alveolar macrophage (AM�) apoptosis by a TNF-�-dependent mechanism. The apoptotic response is postulated to be a defense mechanism, limiting the growth of this intracellular pathogen. Consistent with that model, recent studies showed that t ..."
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Cited by 37 (5 self)
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Infection by Mycobacterium tuberculosis (MTB) induces human alveolar macrophage (AM�) apoptosis by a TNF-�-dependent mechanism. The apoptotic response is postulated to be a defense mechanism, limiting the growth of this intracellular pathogen. Consistent with that model, recent studies showed that the virulent MTB strain H37Rv induces substantially less AM � apoptosis than the attenuated strain H37Ra. We now report that AM � infection with either H37Rv or H37Ra induces comparable levels of TNF- � measured by ELISA but that TNF- � bioactivity is reduced in supernatants of H37Rv-infected AM�. Differential release of soluble TNFR2 (sTNFR2), with formation of inactive TNF-�-TNFR2 complexes accounted for the difference in TNF- � bioactivity in these cultures. Release of sTNFR2 by H37Rv-infected AM � was IL-10 dependent since it was inhibited by neutralizing anti-IL-10 Ab. Thus, the effect of TNF- � produced by AM � following infection can be modulated by virulent MTB, using IL-10 as an upstream mediator. The Journal of Immunology, 1998, 161: 2636–2641.
