Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly malignant myeloma cells up-regulate their Fas-ligand (Fas-L) to escape immune surveillance by Fas(+) cytotoxic cells. Here it is demonstrated that this abnormality is involved in the pathogenesis of the severe anemia associated with progression of multiple myeloma (MM). By measuring Fas and Fas-L in plasma cells and erythroblasts from 19 MM patients and 5 with monoclonal gammopathies of undetermined significance (MGUS), it was found that both Fas-L(+) myeloma cells and Fas(+) erythroid progenitors were significantly increased in patients with stage III MM whose erythroblasts, cultured in the presence of autologous plasma cells or their supernatant, underwent prompt apoptosis as evaluated by propidium iodide staining, the TUNEL assay, and detection of the APO2.7-reactive mitochondrial antigen. Flow cytometry of fresh erythroblasts revealed a considerable expression of the caspases CPP32 and FLICE in both their constitutive proenzymatic forms and in cleaved subunits. By contrast, their intracytoplasmic expression was defective in patients with inactive disease and MGUS controls. The evidence that Fas-L(+) myeloma clones directly prime erythroblast apoptosis in vivo was further supported by the occurrence of fluorescein isothiocyanate-TUNEL(+) erythroblasts juxtaposed to myeloma cells in bone marrow smears. These results strongly suggest that the deregulated apoptosis in myeloma clones plays an active role in the progressive destruction of the erythroid matrix by a cytotoxic mechanism based on up-regulation of Fas-L.
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PMID:Fas-L up-regulation by highly malignant myeloma plasma cells: role in the pathogenesis of anemia and disease progression. 1122 56

We describe a method that has allowed us to measure the synthesis, turnover and assembly of alpha- and beta-erythroid and nonerythroid spectrins in cultured rat hippocampal neurons. For these studies, rat hippocampal cultures containing 74.5-83.0% neurons were established. B-27 (Gibco) supplement has been used to obtain an excellent long-term viability (up to 5 weeks) of hippocampal neurons in culture. For the synthesis, turnover, and assembly experiments the neurons were labeled with [35S]methionine, and chased with 10-fold excess of cold methionine for the turnover experiments. The cells were then lysed and immunoprecipitated with alpha, beta-erythroid, alpha, and beta-nonerythroid spectrin antibodies. Immunoprecipitated [35S]methionine-labeled spectrins of hippocampal neurons grown in vitro produced bands in 5% polyacrylamide minigels strong enough to be detected by the high sensitivity screens of a phosphorimager to generate graphs from which the synthesis or half-lives of alpha, beta-erythroid, alpha, and beta-nonerythroid spectrins were calculated. This method can be used to study the role of calpain, caspase-3, and the ubiquitin-proteasome system on the synthesis and turnover of erythroid and nonerythroid spectrins in resting and depolarized rat hippocampal neurons in culture.
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PMID:Measurement of the synthesis, turnover, and assembly of alpha- and beta-erythroid and nonerythroid spectrins in cultured rat hippocampal neurons. 1122 13

Treatment with granulocyte colony-stimulating factor plus erythropoietin may improve haemoglobin levels in patients with ringsideroblastic anaemia (RARS) and reduce bone marrow apoptosis. We studied bone marrow from 10 RARS patients, two of whom were also investigated after successful treatment. Mononuclear, erythroid and CD34+ cells were analysed with regard to proliferation, apoptosis, clonogenic capacity and oncoprotein expression, in the presence or absence of Fas-agonist, Fas-blocking antibody 2 and caspase-3 inhibitor. During culture, RARS bone marrow cells showed higher spontaneous apoptosis (P < 0.05) and caspase activity (P < 0.05)) than bone marrow cells from healthy donors. Eight out of nine patients had reduced growth of erythroid colony-forming units (CFU-E) (< 10% of control) and granulocyte-macrophage CFU (CFU-GM) (< 50% of control) from CD34+ cells. Fas ligation increased apoptosis and decreased colony growth equally in RARS and controls, but caused significantly more caspase activation in RARS (P < 0.01). Fas-blocking antibody showed no significant inhibitory effect on spontaneous apoptosis or ineffective haematopoiesis, as measured using phosphatidylserine exposure, the terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labelling technique, caspase activity or clonogenic growth. Caspase inhibition reduced apoptosis, increased proliferation and enhanced erythroid colony growth from CD34+ cells in RARS, but showed no effect on normal cells. CFU-E improved > 1000% after successful treatment. Thus, erythroid apoptosis in RARS is initiated at the CD34+ level and growth factor treatment may improve stem cell function. Enhanced caspase activation at the stem cell level, albeit not mediated through endogenous activation of the Fas receptor, contributes to the erythroid apoptosis in RARS.
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PMID:Apoptosis in refractory anaemia with ringed sideroblasts is initiated at the stem cell level and associated with increased activation of caspases. 1126 77

Activin A, one member of the transforming growth factor (TGF)-beta superfamily, is known to be a commitment factor for cell death and differentiation. In the present study, we demonstrate that human chronic myeloid leukemia (CML) cell lines, KU812 and K562 cells, either induced apoptosis or differentiation, respectively, by treatment with activin A. During these cell fate decisive events caused by activin A, rapid and transient up-regulation of Mcl-1 was observed in both cell lines. In activin A-induced apoptosis of KU812 cells, continuous up-regulation of Bax was observed. After the decrease in Mcl-1 expression had occurred, activation of caspase-9 and caspase-3 and cleavage of DFF45 were shown to take place in KU812 cells, resulting in the fragmentation of the genomic DNA of the cells. In contrast, the down-regulation of Mcl-1 without up-regulation of Bax caused accumulation of hemoglobin (Hb) contents in activin A-treated K562 cells. Interestingly, erythropoietin (EPO) prevented activin A-induced apoptosis with continuous expression of Mcl-1 and caused KU812 cells to undergo erythroid differentiation. To address the role of Mcl-1 in activin A-treated CML cells, KU812 and K562 cells were stably transfected with cDNA encoding Mcl-1 (designated as KU812/mcl and K562/mcl cells). As in combined effect of activin A and EPO on the parental KU812 cells, activin A induced differentiation, but not apoptosis, of KU812/mcl cells without modulating Bax levels. Activin A-treated K562/mcl cells, as well as parental cells, were only differentiated to erythroid cells. These results suggest that Mcl-1 is an early inducible gene activated by the activin A signaling pathway for both cellular differentiation and apoptosis, and continuous expression of Mcl-1 may be contributed to differentiation signals to the erythroid lineage in CML cells.
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PMID:Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML cells. 1131 4

Treatment with granulocyte colony-stimulating factor (G-CSF) plus erythropoietin may synergistically improve hemoglobin levels and reduce bone marrow apoptosis in patients with refractory anemia with ringed sideroblasts (RARS). Fas-induced caspase activity is increased in RARS bone marrow cells. We showed that G-CSF significantly reduced Fas-mediated caspase-8 and caspase-3-like activity and the degree of nuclear apoptotic changes in bone marrow from nine RARS patients. A decrease in mitochondrial membrane potential and an increase in intracellular reactive oxygen species occurred in Fas-treated cells, but became significant only 24 h after changes in caspase activity and decrease in proliferation. G-CSF also reduced the magnitude of these late apoptotic changes. In CD34-selected normal cells, G-CSF induced myeloid colony growth, and an overall small decrease in the number of erythroid colonies. By contrast, G-CSF induced a 33-263% increase of erythroid colony formation in CD34+ cells from four of five RARS patients with severely reduced erythroid growth, while the normal or slightly reduced erythroid growth of three other patients was not influenced by G-CSF. This study suggests that G-CSF may reduce the pathologically increased caspase activity and concomitant apoptotic changes, and promote erythroid growth and differentiation of stem cells from RARS patients. Our data support the clinical benefit of G-CSF in this subgroup of myelodysplastic syndromes.
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PMID:Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringed sideroblasts. 1136 34

Although a number of increased CSF proteins have been correlated with brain damage and outcome after traumatic brain injury (TBI), a major limitation of currently tested biomarkers is a lack of specificity for defining neuropathological cascades. Identification of surrogate biomarkers that are elevated in CSF in response to brain injury and that offer insight into one or more pathological neurochemical events will provide critical information for appropriate administration of therapeutic compounds for treatment of TBI patients. Non-erythroid alpha II-spectrin is a cytoskeletal protein that is a substrate of both calpain and caspase-3 cysteine proteases. As we have previously demonstrated, cleavage of alpha II-spectrin by calpain and caspase-3 results in accumulation of protease-specific spectrin breakdown products (SBDPs) that can be used to monitor the magnitude and temporal duration of protease activation. However, accumulation of alpha II-spectrin and alpha II-SBDPs in CSF after TBI has never been examined. Following a moderate level (2.0 mm) of controlled cortical impact TBI in rodents, native alpha II-spectrin protein was decreased in brain tissue and increased in CSF from 24 h to 72 h after injury. In addition, calpain-specific SBDPs were observed to increase in both brain and CSF after injury. Increases in the calpain-specific 145 kDa SBDP in CSF were 244%, 530% and 665% of sham-injured control animals at 24 h, 48 h and 72 h after TBI, respectively. The caspase-3-specific SBDP was observed to increase in CSF in some animals but to a lesser degree. Importantly, levels of these proteins were undetectable in CSF of uninjured control rats. These results indicate that detection of alpha II-spectrin and alpha II-SBDPs is a powerful discriminator of outcome and protease activation after TBI. In accord with our previous studies, results also indicate that calpain may be a more important effector of cell death after moderate TBI than caspase-3.
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PMID:Accumulation of non-erythroid alpha II-spectrin and calpain-cleaved alpha II-spectrin breakdown products in cerebrospinal fluid after traumatic brain injury in rats. 1157 38

Giant proerythroblasts are hallmarks of human parvovirus B19 infection. We attempted to characterize these cells in 5 patients with parvovirus B19-induced pure red cell aplasia using immunostaining of paraffin-embedded bone marrow sections with antibodies against erythroid-lineage-specific proteins, viral capsid antigen VP-1, and apoptosis- and cell-cycle-related proteins. Giant proerythroblasts are immunohistochemically consistent with early erythroid precursors of cells in the differentiation stage of CD34-, cytoplasmic spectrin+, glycophorin A-, and band-3-. VP-1 was expressed in the nucleus and cytoplasm of small- to medium-sized spectrin+ erythroid cells but not in giant proerythroblasts. The giant proerythroblasts displayed nuclear staining for p53 (41%+/-16%) and Ki-67 antigen (100%+/-0%) and cytoplasmic staining for Bax (65%+/-11%) and procaspase-3 (78%+/-10%), whereas they were not stained for p21Wafl/Cip1, active form of caspase-3, or terminal deoxynucleotidyltransferase-mediated deoxyuridine nick-end labeling (TUNEL). Antiapoptotic proteins, Bcl-2 and Mcl-1, were not expressed in the giant cells, and Bcl-x was infrequently expressed in these cells (11%+/-4%). These immunohistochemical findings suggest that giant proerythroblasts are proliferating erythroid precursors with accumulation of nonfunctional p53.
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PMID:Expression of p53 and Ki-67 antigen in bone marrow giant proerythroblasts associated with human parvovirus B19 infection. 1159 14

The involvement of MAPK pathways in differentiation, proliferation and survival was investigated by comparing Epo and GM-CSF signalling in human factor-dependent myeloerythroid TF-1 cells with abnormal Epo-R. GM-CSF withdrawal induced cell-cycle arrest and apoptosis accompanied by increased caspase-3 activity, DNA degradation and reduced expression of the antiapoptotic Bcl-2 and Bcl-xl proteins. Readministration of GM-CSF but not Epo reversed these processes and induced proliferation. The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. In contrast, Epo failed to activate the Raf-1/ERK1/2 MAPK pathway or to induce Egr-1 and/or c-Fos expression, while it induced erythroid differentiation in GM-CSF-deprived cells. In addition, the Epo-induced haemoglobin production was inhibited in the presence of GM-CSF. These results demonstrate that the activation of MAPK cascade is not necessary for Epo-induced haemoglobin production in TF-1 cells and suggest a negative cross-talk between the signalling of GM-CSF-stimulated cell proliferation and Epo-induced erythroid differentiation.
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PMID:Activation of Raf/ERK1/2 MAP kinase pathway is involved in GM-CSF-induced proliferation and survival but not in erythropoietin-induced differentiation of TF-1 cells. 1160 85

Previous studies have demonstrated that SH2-containing inositol phosphatase (SHIP) is involved in the control of B cell, myeloid cell and macrophage activation and proliferation. The goal of the present study was to examine the role of SHIP during proliferation and apoptosis in cells of the erythroid lineage. Wild-type and catalytically inactive SHIP proteins were overexpressed in the erythropoietin (EPO)-dependent cell line AS-E2. Stable overexpression of catalytically inactive SHIP decreased proliferation and resulted in prolonged activation of the extracellular signal-regulated protein kinases ERK1/2 and protein kinase B (PKB), while wild-type SHIP did not affect EPO-mediated proliferation or phosphorylation of ERK and PKB. When AS-E2 cells were EPO deprived a significant increase in apoptosis was observed in clones overexpressing wild type. Mutational analysis showed that this increase in apoptosis was independent of the enzymatic activity of SHIP. The enhanced apoptosis due to overexpression of SHIP was associated with an increase in caspase-3 and -9 activity, without a distinct effect on caspase-8 activity or mitochondrial depolarization. Moreover, in cells overexpressing SHIP apoptosis could be reduced by a caspase-3 inhibitor. These data demonstrate that in the erythroid cell line AS-E2 overexpression of catalytically inactive SHIP reduced proliferation, while overexpression of wild-type SHIP had no effect. Furthermore, overexpression of SHIP enhanced apoptosis during growth factor deprivation by inducing specific caspase cascades, which are regulated independently of the 5-phosphatase activity of SHIP.
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PMID:Effects of overexpression of the SH2-containing inositol phosphatase SHIP on proliferation and apoptosis of erythroid AS-E2 cells. 1168 17

The adenosine deaminase inhibitor 2'-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cells in the presence of either 2'-deoxyadenosine (dAdo) or its analog adenine arabinoside (araA). The concentration of dCF required to induce apoptosis of monocytoid leukemia cells is much lower than that required for myeloid, erythroid, or lymphoma cells. dATP effectively induces caspase-3 activation in cytosol from monocytoid cells, but not in that from non-monocytoid cells, suggesting that dATP-dependent caspase-3 activation is involved in the preferential induction of apoptosis in monocytoid leukemia cells. Athymic nude mice inoculated with human monocytoid leukemia U937 cells show significantly prolonged survival following combined treatment with dCF and araA. The clinical usefulness of the combination of adenosine deaminase inhibitor and dAdo analog is discussed.
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PMID:A novel therapeutic strategy against monocytic leukemia with deoxyadenosine analogs and adenosine deaminase inhibitors. 1169 50


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