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Jedi-1 and MEGF10 signal engulfment of apoptotic neurons through the tyrosine kinase Syk.
Scheib JL, Sullivan CS, Carter BD
(2012) J Neurosci 32: 13022-31
MeSH Terms: Amino Acid Motifs, Animals, Apoptosis, Arabidopsis Proteins, Cell Count, Cells, Cultured, Coculture Techniques, Embryo, Mammalian, Enzyme Inhibitors, Female, Ganglia, Spinal, Gene Expression Regulation, Green Fluorescent Proteins, Humans, Immunoprecipitation, Immunoreceptor Tyrosine-Based Activation Motif, Intracellular Signaling Peptides and Proteins, Intramolecular Transferases, Male, Membrane Proteins, Mice, Microglia, Mutagenesis, Site-Directed, Mutation, Neurons, Niacinamide, Phagocytosis, Phosphorylation, Protein-Tyrosine Kinases, Pyrimidines, RNA, Small Interfering, Signal Transduction, Staurosporine, Syk Kinase, Transfection
Show Abstract · Added March 5, 2014
During the development of the peripheral nervous system there is extensive apoptosis, and these neuronal corpses need to be cleared to prevent an inflammatory response. Recently, Jedi-1 and MEGF10, both expressed in glial precursor cells, were identified in mouse as having an essential role in this phagocytosis (Wu et al., 2009); however, the mechanisms by which they promote engulfment remained unknown. Both Jedi-1 and MEGF10 are homologous to the Drosophila melanogaster receptor Draper, which mediates engulfment through activation of the tyrosine kinase Shark. Here, we identify Syk, the mammalian homolog of Shark, as a signal transducer for both Jedi-1 and MEGF10. Syk interacted with each receptor independently through the immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular domains. The interaction was enhanced by phosphorylation of the tyrosines in the ITAMs by Src family kinases (SFKs). Jedi association with Syk and activation of the kinase was also induced by exposure to dead cells. Expression of either Jedi-1 or MEGF10 in HeLa cells facilitated engulfment of carboxylated microspheres to a similar extent, and there was no additive effect when they were coexpressed. Mutation of the ITAM tyrosines of Jedi-1 and MEGF10 prevented engulfment. The SFK inhibitor PP2 or a selective Syk inhibitor (BAY 61-3606) also blocked engulfment. Similarly, in cocultures of glial precursors and dying sensory neurons from embryonic mice, addition of PP2 or knock down of endogenous Syk decreased the phagocytosis of apoptotic neurons. These results indicate that both Jedi-1 and MEGF10 can mediate phagocytosis independently through the recruitment of Syk.
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35 MeSH Terms
Characterization of cell clones isolated from hypoxia-selected renal proximal tubular cells.
Brooks C, Wang J, Yang T, Dong Z
(2007) Am J Physiol Renal Physiol 292: F243-52
MeSH Terms: Adenosine Triphosphate, Animals, Apoptosis, Azides, Cadherins, Caspases, Cell Hypoxia, Cisplatin, Clone Cells, Cytochromes c, Enzyme Activation, Epithelial Cells, Fluorescent Antibody Technique, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Kidney Tubules, Proximal, Phenotype, Protein Transport, Rats, Staurosporine, Subcellular Fractions, bcl-2-Associated X Protein, bcl-X Protein
Show Abstract · Added September 12, 2016
Under hypoxia, some cells survive and others are irreversibly injured and die. The factors that determine cell fate under stress remain largely unknown. We recently selected death-resistant cells via repeated episodes of hypoxia. In the present study, 80 clones were isolated from the selected cells and their response to apoptotic injury was characterized. Compared with the wild-type cells, the isolated clones showed a general resistance to apoptosis: 13 were extremely resistant to azide-induced apoptosis, 10 to staurosporine, and 9 to cisplatin. The cell clones that most consistently demonstrated resistance or sensitivity to injury were further studied for their response to azide treatment. Azide induced comparable ATP depletion in these clones and wild-type cells. Hypoxia inducible factor-1 (HIF-1) was upregulated in several clones, but the upregulation did not correlate with cell death resistance. The selected clones maintained an epithelial phenotype, showing typical epithelial morphology, forming "domes" at high density, and expressing E-cadherin. Azide-induced Bax translocation and cytochrome c release, two critical mitochondrial events of apoptosis, were abrogated in death-resistant clones. In addition, cell lysates isolated from these clones showed lower caspase activation on addition of exogenous cytochrome c. Bax, Bak, and Bid expression in these clones was similar to that in wild-type cells, whereas Bcl-2 expression was higher in all the selected clones and, interestingly, Bcl-xL was markedly upregulated in the most death-resistant clones. The results suggest that apoptotic resistance of the selected clones is not determined by a single factor or molecule but, rather, by various alterations at the core apoptotic pathway.
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23 MeSH Terms
Involvement of the ubiquitin pathway in decreasing Ku70 levels in response to drug-induced apoptosis.
Gama V, Yoshida T, Gomez JA, Basile DP, Mayo LD, Haas AL, Matsuyama S
(2006) Exp Cell Res 312: 488-99
MeSH Terms: Acetylcysteine, Amino Acid Chloromethyl Ketones, Antigens, Nuclear, Apoptosis, Caspase Inhibitors, Cell Line, Cysteine Proteinase Inhibitors, DNA-Binding Proteins, Doxorubicin, Gene Expression, HeLa Cells, Humans, Ku Autoantigen, Leupeptins, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Signal Transduction, Staurosporine, Ubiquitin, Ubiquitin-Protein Ligase Complexes
Show Abstract · Added October 26, 2015
Ku70 plays an important role in DNA damage repair and prevention of cell death. Previously, we reported that apoptosis caused a decrease in cellular Ku70 levels. In this study, we analyzed the mechanism of how Ku70 levels decrease during drug-induced apoptosis. In HeLa cells, staurosporin (STS) caused a decrease in Ku70 levels without significantly affecting Ku70 mRNA levels. We found that Ku70 protein was highly ubiquitinated in various cell types, such as HeLa, HEK293T, Dami (a megakaryocytic cell line), endothelial, and rat kidney cells. An increase in ubiquitinated Ku70 protein was observed in apoptotic cells, and proteasome inhibitors attenuated the decrease in Ku70 levels in apoptotic cells. These results suggest that the ubiquitin-proteasome proteolytic pathway plays a role in decreasing Ku70 levels in apoptotic cells. Ku70 forms a heterodimer with Ku80, which is required for the DNA repair activity of Ku proteins. We also found that Ku80 levels decreased in apoptotic cells and that Ku80 is a target of ubiquitin. Ubiquitinated Ku70 was not found in the Ku70-Ku80 heterodimer, suggesting that modification by ubiquitin inhibits Ku heterodimer formation. We propose that the ubiquitin-dependent modification of Ku70 plays an important role in the control of cellular levels of Ku70.
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20 MeSH Terms
Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice.
Liu J, Thewke DP, Su YR, Linton MF, Fazio S, Sinensky MS
(2005) Arterioscler Thromb Vasc Biol 25: 174-9
MeSH Terms: Animals, Apoptosis, Arteriosclerosis, Bone Marrow Cells, Bone Marrow Transplantation, Cholesterol, Lipoproteins, Lipoproteins, LDL, Lymphocyte Count, Lymphocytes, Macrophages, Peritoneal, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Proto-Oncogene Proteins c-bcl-2, Receptors, LDL, Staurosporine, Triglycerides, bcl-2-Associated X Protein
Show Abstract · Added May 27, 2014
OBJECTIVE - The majority of apoptotic cells in atherosclerotic lesions are macrophages. However, the pathogenic role of macrophage apoptosis in the development of atherosclerosis remains unclear. Elevated expression of Bax, one of the pivotal proapoptotic proteins of the Bcl-2 family, has been found in human atherosclerotic plaques. Activation of Bax also occurs in free cholesterol-loaded and oxysterol-treated mouse macrophages. In this study, we examined the effect of Bax deficiency in bone marrow-derived leukocytes on the development of atherosclerosis in low-density lipoprotein receptor-null (LDLR-/-) mice.
METHODS AND RESULTS - Fourteen 8-week-old male LDLR-/- mice were lethally irradiated and reconstituted with either wild-type (WT) C57BL6 or Bax-null (Bax-/-) bone marrow. Three weeks later, the mice were challenged with a Western diet for 10 weeks. No differences were found in the plasma cholesterol level between the WT and Bax-/- group. However, quantitation of cross sections from proximal aorta revealed a 49.2% increase (P=0.0259) in the mean lesion area of the Bax-/- group compared with the WT group. A 53% decrease in apoptotic macrophages in the Bax-/- group was found by TUNEL staining (P<0.05).
CONCLUSIONS - The reduction of apoptotic activity in macrophages stimulates atherosclerosis in LDLR-/- mice, which is consistent with the hypothesis that macrophage apoptosis suppresses the development of atherosclerosis.
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20 MeSH Terms
Adhesion-associated and PKC-modulated changes in serine/threonine phosphorylation of p120-catenin.
Xia X, Mariner DJ, Reynolds AB
(2003) Biochemistry 42: 9195-204
MeSH Terms: 3T3 Cells, Amino Acid Sequence, Animals, Catenins, Cell Adhesion, Cell Adhesion Molecules, Cell Membrane Permeability, Conserved Sequence, Enzyme Activation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Mice, Models, Biological, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphoamino Acids, Phosphoproteins, Phosphorylation, Protein Kinase C, Serine, Signal Transduction, Species Specificity, Staurosporine, Substrate Specificity, Threonine, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
p120-catenin (p120) was originally identified as a tyrosine kinase substrate, and subsequently shown to regulate cadherin-mediated cell-cell adhesion. Binding of the p120 Arm domain to E-cadherin appears to be necessary to maintain adequate cadherin levels for strong adhesion. In contrast, the sequence amino-terminal to the Arm domain confers a negative regulatory function that is likely to be modulated by phosphorylation. Several agents that induce rapid changes in cell-cell adhesion, including PDBu, histamine, thrombin, and LPA, result in significant changes in p120 S/T phosphorylation. In some cases, these changes are PKC-dependent, but the relationship among adhesion, PKC activation, and p120 phosphorylation is unclear, in part because the relevant p120 phosphorylation sites are unknown. As a crucial step toward directly identifying the function of these modifications in adhesion, we have used two-dimensional tryptic mapping and site-directed mutagenesis to pinpoint the constitutive and PKC-modulated sites of p120 S/T phosphorylation. Of eight sites that have been identified, two were selectively phosphorylated in vitro by GSK3 beta, but in vivo treatment of cells with GSK3 beta inhibitors did not eliminate these sites. PKC stimulation in vivo induced potent dephosphorylation at S268, and partial dephosphorylation of several additional sites. Surprisingly, PKC also strongly induced phosphorylation at S873. These data directly link PKC activation to specific changes in p120 phosphorylation, and identify the target sites associated with the mechanism of PKC-dependent adhesive changes induced by agents such as histamine and PDBu.
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27 MeSH Terms
Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis.
Fingleton B, Vargo-Gogola T, Crawford HC, Matrisian LM
(2001) Neoplasia 3: 459-68
MeSH Terms: Animals, Antibodies, Monoclonal, Apoptosis, Breast, Clone Cells, Concanavalin A, Cycloheximide, DNA, Complementary, Enzyme Induction, Enzyme Inhibitors, Epithelial Cells, Fas Ligand Protein, Female, Humans, Interleukin-2, Killer Cells, Natural, Lymphocyte Activation, Male, Mammary Glands, Animal, Matrix Metalloproteinase 7, Membrane Glycoproteins, Mice, Mitomycin, Protein Synthesis Inhibitors, Rabbits, Rats, Recombinant Fusion Proteins, Spleen, Staurosporine, T-Lymphocytes, Transfection, fas Receptor
Show Abstract · Added March 5, 2014
The matrix metalloproteinase matrilysin (MMP-7) has been demonstrated to contribute to tumor development. We have shown previously that members of the TNF family of apoptosis-inducing proteins are substrates for this enzyme, resulting in increased death pathway signaling. The goal of the current study was to reconcile the proapoptotic and tumor-promoting functions of matrilysin. In the human HBL100 and murine NMuMG cell lines that represent early stages of tumor progression and that express both Fas ligand and its receptor, exposure to matrilysin results in cell death that can be blocked by FasL neutralizing antibodies. Constitutive expression of matrilysin in these cell lines selects for cells with reduced sensitivity to Fas-mediated apoptosis as demonstrated both with a receptor-activating antibody and with in vitro activated splenocytes. Matrilysin-expressing cells are also significantly less sensitive to chemical inducers of apoptosis. We propose that the expression of matrilysin that has been reported at early stages in various tumor types can act to select cells with a significantly decreased chance of removal due to immune surveillance. As a result, these cells are more likely to acquire additional genetic modifications and develop further as tumors.
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32 MeSH Terms
Localization of human Cdc25C is regulated both by nuclear export and 14-3-3 protein binding.
Graves PR, Lovly CM, Uy GL, Piwnica-Worms H
(2001) Oncogene 20: 1839-51
MeSH Terms: 14-3-3 Proteins, Active Transport, Cell Nucleus, Alkaloids, Amino Acid Sequence, Cell Cycle Proteins, Cytoplasm, Fatty Acids, Unsaturated, HeLa Cells, Humans, Molecular Sequence Data, Protein Binding, Staurosporine, Tyrosine 3-Monooxygenase, cdc25 Phosphatases
Show Abstract · Added March 5, 2014
Entry into mitosis requires activation of the Cdc2 protein kinase by the Cdc25C protein phosphatase. The interactions between Cdc2 and Cdc25C are negatively regulated throughout interphase and in response to G2 checkpoint activation. This is accomplished in part by maintaining the Cdc25 phosphatase in a phosphorylated form that binds 14-3-3 proteins. Here we report that 14-3-3 binding regulates the intracellular trafficking of Cdc25C. Although primarily cytoplasmic, Cdc25C accumulated in the nuclei of leptomycin B (LMB)-treated cells, indicating that Cdc25C is actively exported out of the nucleus. A mutant of Cdc25C that is unable to bind 14-3-3 was partially nuclear in the absence of LMB and its nuclear accumulation was greatly enhanced by LMB-treatment. A nuclear export signal (NES) was identified within the amino terminus of Cdc25C. Although mutation of the NES did not effect 14-3-3 binding, it did cause nuclear accumulation of Cdc25C. These results demonstrate that 14-3-3 binding is dispensable for the nuclear export of Cdc25C. However, complete nuclear accumulation of Cdc25C required loss of both NES function and 14-3-3 binding and this was accomplished both pharmacologically and by mutation. These findings suggest that the nuclear export of Cdc25C is mediated by an intrinsic NES and that 14-3-3 binding negatively regulates nuclear import.
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14 MeSH Terms
p120(ctn) acts as an inhibitory regulator of cadherin function in colon carcinoma cells.
Aono S, Nakagawa S, Reynolds AB, Takeichi M
(1999) J Cell Biol 145: 551-62
MeSH Terms: Alkaloids, Benzoquinones, Binding Sites, Cadherins, Catenins, Cell Adhesion Molecules, Cell Aggregation, Cytoskeletal Proteins, DNA Primers, DNA, Complementary, Electrophoresis, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, Genistein, HT29 Cells, Humans, Kidney, Lactams, Macrocyclic, Membrane Glycoproteins, Mucin-1, Naphthalenes, Phosphoproteins, Quinones, Rifabutin, Staurosporine, Trans-Activators, Transfection, alpha Catenin, beta Catenin
Show Abstract · Added March 5, 2014
p120(ctn) binds to the cytoplasmic domain of cadherins but its role is poorly understood. Colo 205 cells grow as dispersed cells despite their normal expression of E-cadherin and catenins. However, in these cells we can induce typical E-cadherin-dependent aggregation by treatment with staurosporine or trypsin. These treatments concomitantly induce an electrophoretic mobility shift of p120(ctn) to a faster position. To investigate whether p120(ctn) plays a role in this cadherin reactivation process, we transfected Colo 205 cells with a series of p120(ctn) deletion constructs. Notably, expression of NH2-terminally deleted p120(ctn) induced aggregation. Similar effects were observed when these constructs were introduced into HT-29 cells. When a mutant N-cadherin lacking the p120(ctn)-binding site was introduced into Colo 205 cells, this molecule also induced cell aggregation, indicating that cadherins can function normally if they do not bind to p120(ctn). These findings suggest that in Colo 205 cells, a signaling mechanism exists to modify a biochemical state of p120(ctn) and the modified p120(ctn) blocks the cadherin system. The NH2 terminus-deleted p120(ctn) appears to compete with the endogenous p120(ctn) to abolish the adhesion-blocking action.
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29 MeSH Terms
The role of cadherin endocytosis in endothelial barrier regulation: involvement of protein kinase C and actin-cadherin interactions.
Alexander JS, Jackson SA, Chaney E, Kevil CG, Haselton FR
(1998) Inflammation 22: 419-33
MeSH Terms: Actins, Animals, Cadherins, Calcium, Capillary Permeability, Cattle, Cells, Cultured, Cytochalasin D, Cytoskeleton, Endocytosis, Endothelium, Vascular, Enzyme Inhibitors, Protein Kinase C, Staurosporine, Trypsin
Show Abstract · Added May 27, 2014
We have previously reported that exposure of endothelial monolayers to low (0.12 mM) extracellular calcium significantly decreased the endothelial solute barrier, and that this effect was reversed by restoring 'normal' (1.2 mM) calcium (1). This effect was shown to be dependent on cadherins, however the molecular mechanisms through which barrier was altered by low calcium were not characterized. Here we investigated the mechanism of increased endothelial permeability produced by low calcium exposure. Endothelial permeability was significantly increased by exposure to low (0.12 mM) calcium; this effect was attenuated by pre-treatment with the protein kinase C (PKC) inhibitor, staurosporine (2 x 10(-7) M) for 30 min. Cell border retraction and gap formation produced by low calcium was also prevented by staurosporine. Treatment of monolayers with 0.12 mM calcium also stimulated the endocytosis of endothelial cadherins. This low calcium mediated cadherin endocytosis was also prevented by pretreatment with staurosporine. Low calcium mediated endocytosis was also prevented by the actin filament toxin, cytochalasin D (1 ug/ml, 30 min). We conclude that the mechanism of low calcium mediated loss of endothelial barrier function is mediated in part by a PKC dependent endocytosis of endothelial cadherins, which may involve interactions with the actin cytoskeleton. Physiological regulation of the in vivo endothelial barrier may also involve PKC dependent-actin mediated endocytosis of cadherin junctional elements.
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15 MeSH Terms
Comparison of apoptosis in wild-type and Fas-resistant cells: chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions.
Eischen CM, Kottke TJ, Martins LM, Basi GS, Tung JS, Earnshaw WC, Leibson PJ, Kaufmann SH
(1997) Blood 90: 935-43
MeSH Terms: Affinity Labels, Antineoplastic Agents, Antineoplastic Agents, Phytogenic, Apoptosis, Biotin, Camptothecin, Caspase 3, Caspase 7, Caspases, Cisplatin, Cysteine Endopeptidases, Doxorubicin, Drug Resistance, Neoplasm, Enzyme Inhibitors, Etoposide, Fas Ligand Protein, Flow Cytometry, Humans, Lamin Type B, Lamins, Leukemia-Lymphoma, Adult T-Cell, Membrane Glycoproteins, Methotrexate, Neoplasm Proteins, Nuclear Proteins, Oligopeptides, Poly(ADP-ribose) Polymerases, Staurosporine, Topoisomerase II Inhibitors, Topotecan, Tumor Cells, Cultured, fas Receptor
Show Abstract · Added March 5, 2014
The Fas/Fas ligand (FasL) pathway is widely involved in apoptotic cell death in lymphoid and nonlymphoid cells. It has recently been postulated that many chemotherapeutic agents also induce cell death by activating the Fas/FasL pathway. In the present study we compared apoptotic pathways induced by anti-Fas or chemotherapeutic agents in the Jurkat human T-cell leukemia line. Immunoblotting showed that treatment of wild-type Jurkat cells with anti-Fas or the topoisomerase II-directed agent etoposide resulted in proteolytic cleavage of precursors for the cysteine-dependent aspartate-directed proteases caspase-3 and caspase-7 and degradation of the caspase substrates poly(ADP-ribose) polymerase (PARP) and lamin B1. Likewise, affinity labeling with N-(N(alpha)-benzyloxycarbonylglutamyl-N(epsilon)-biotinyllysyl+ ++)aspartic acid [(2,6-dimethyl-benzoyl)oxy]methyl ketone [Z-EK(bio)D-amok] labeled the same five active caspase species after each treatment, suggesting that the same downstream apoptotic pathways have been activated by anti-Fas and etoposide. Treatment with ZB4, an antibody that inhibits Fas-mediated cell death, failed to block etoposide-induced apoptosis, raising the possibility that etoposide does not initiate apoptosis through Fas/FasL interactions. To further explore the relationship between Fas- and chemotherapy-induced apoptosis, Fas-resistant Jurkat cells were treated with various chemotherapeutic agents. Multiple independently derived Fas-resistant Jurkat lines underwent apoptosis that was indistinguishable from that of the Fas-sensitive parental cells after treatment with etoposide, doxorubicin, topotecan, cisplatin, methotrexate, staurosporine, or gamma-irradiation. These results indicate that antineoplastic treatments induce apoptosis through a Fas-independent pathway even though Fas- and chemotherapy-induced pathways converge on common downstream apoptotic effector molecules.
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32 MeSH Terms