UNIPROT:P42574 - FACTA Search

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

Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematopoietic cytokines transduce cell survival signals, which are distinct from the signals necessary for the stimulation of DNA synthesis. Recently, the Ras and phosphatidylinositol 3-kinase pathways have been shown to play important roles in preventing apoptosis in various cell types, e.g. hematopoietic cells and neuronal cells. Withdrawal of cytokine(s), in turn, results in rapid inactivation of these survival pathways and eventually leads to cell death accompanied by the hallmarks of apoptosis. However, the mechanism of cell death caused by cytokine deprivation has not been fully elucidated. In this study, we demonstrate that caspase-3/CPP32, a member of the caspase/interleukin-1beta-converting enzyme family, is activated upon interleukin (IL)-3 deprivation in IL-3-dependent cells as well as IL-2 deprivation in IL-2-dependent cells. In addition, poly(ADP-ribose) polymerase, a cellular substrate for the caspase family proteases, was degraded into apoptotic fragments in both cell lines after cytokine removal. Furthermore, inhibition of a caspase family protease by synthetic peptides suppressed apoptotic death. These results indicate that the activation of a caspase-like protease(s) is required for the progression of apoptosis following cytokine deprivation. However, readdition of IL-3 did not restore the proliferative potential of the cells that survived in the presence of the peptide inhibitor after IL-3 depletion. Therefore, cellular commitment to apoptosis appears to precede the activation of a caspase-like protease(s).
...
PMID:Requirement of the caspase-3/CPP32 protease cascade for apoptotic death following cytokine deprivation in hematopoietic cells. 928 12

Both T cells and natural killer (NK) cells express CD2, the target of an alternative activation pathway that induces the proliferation of both cell types. The mitogenic response to CD2 ligation requires the co-expression of CD3:TCR in T cells and FcgammaRIII in NK cells, suggesting that these receptors are involved in transducing the response initiated by CD2. The ability of FcgammaRIII to trigger the activation-induced death of IL-2-primed NK cells led us to investigate the potential for CD2 to trigger activation-induced NK cell death. Our results reveal that the same anti-CD2 monoclonal antibodies (mAb) that activate freshly isolated NK cells induce apoptosis in IL-2-primed NK cells. CD2-induced apoptosis results in chromatin condensation, DNA fragmentation and cleavage of caspase-3. Activation-induced NK cell death triggered by CD2 ligation is extremely rapid (DNA fragmentation is first observed at 90 min) and it is not inhibited by neutralizing antibodies reactive with TNF-alpha or Fas ligand. Whereas mAb reactive with distinct CD2 epitopes (i.e. T11.1, T11.2, and T11.3) are required for activation-induced T cell death, mAb reactive with a single CD2 epitope are sufficient for activation-induced NK cell death. The ability of CD2, CD16, and CD94 to induce apoptosis in IL-2-primed lymphocytes suggests that cytokine priming changes the response to a signaling cascade that is common to each of these activation receptors.
...
PMID:Activation-induced NK cell death triggered by CD2 stimulation. 956 69

The caspase family of proteases has previously been implicated in the biochemical cascade leading to apoptotic cell death. Recently caspase-3 was reported to be cleaved into its catalytically active subunits (17 and 13 kDa) following phytohemagglutinin (PHA) activation of peripheral blood mononuclear cells (C. Miossec et al., J. Biol. Chem. 272, 13459-13462). More recently, J. M. Zapata and colleagues (J. Biol. Chem. 273, 6916-6920, 1998), however, proposed that caspase-3 activity detected during T-cell activation was due to a methodological artifact related to the composition of the cell lysis buffer. Here we show that in PHA-activated Jurkat T-cells using the recommended lysis buffer detailed by Zapata et al., a caspase-3-like protease is activated and is accompanied by cleavage of PARP and alpha-spectrin into cleavage products suggestive of caspase-3 proteolytic activation. LDH release did not increase following PHA stimulation in this paradigm. Two caspase inhibitors, carbobenzoxy-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-D-DCB) and acetyl-Asp-Glu-Val-Asp-CHO, blocked IL-2 release in a dose-dependent manner. Caspase-3-like protease-generated PARP and alpha-spectrin breakdown product formation was also reduced by Z-D-DCB. In addition, Jurkat T-cells costimulated with anti-CD3 plus anti-CD28 produced significant levels of IL-2 that were also blocked by these caspase inhibitors. Importantly, IL-2 was determined in cell culture supernatants, thus avoiding a cell lysis step that might have enabled activation of caspase-3 by granzyme B. Collectively, these data support the role of caspase-3-like protease activity in Jurkat T-cell activation and demonstrate that caspase-3 like activity is necessary for IL-2 release in PHA-activated and anti-CD3/anti-CD28 costimulated Jurkat T-cells.
...
PMID:Caspase-3-like activity is necessary for IL-2 release in activated Jurkat T-cells. 977 Mar 73

The modulation of the cytotoxic effects of an anthracyclin by CD40L was investigated in five non-Hodgkin's lymphoma (NHL) cell lines (Daudi, Raji, BJAB, BL36, BL70). Incubation with doxorubicin (DOX) increased in a dose-dependent manner the percentage of apoptosis in NHL cells. Coculture with irradiated L cells expressing CD40L (CD40L L cells), but not CDw32 (CDw32 L cells), significantly reduced (33% to 89%) the percentage of apoptosis in all five cell lines treated with 0.1 to 0.5 microgram/mL of DOX, but in only three cell lines at 1 microgram/mL. Interleukin-10 (IL-10), IL-6, IL-2, or tumor necrosis factor (TNF) induced no additive protective effects with CD40L L cells. In all five cell lines, DOX induced a concentration-dependent increase of the activity of the cysteine-protease caspase 3. Coculture with CD40L L cells, but not with CDw32 L cells, inhibited (38% to 100%) the activation of caspase 3 induced by 0.1 to 0.5 microgram/mL of DOX in all five NHL cell lines, but in only two cell lines at 1 microgram/mL. Finally, the antiproliferative effect of 0.1 to 0.5 microgram/mL concentrations of DOX was also partially abrogated on coculture with CD40L L cells in all five cell lines, but in only two cell lines at 1 microgram/mL. Cytokines, either alone or in combination with CD40L L cells, did not affect DOX-induced inhibition of proliferation. These results indicate that CD40L inhibits the apoptosis and antiproliferative effect induced by DOX and interferes with caspase 3 activation in B NHL cell lines.
...
PMID:Resistance to cytotoxic chemotherapy induced by CD40 ligand in lymphoma cells. 978 77

Here we identify the hematopoietic proto-oncogene Vav1 as a caspase substrate during apoptosis in lymphoid cells. Cleavage of Vav1 is prevented by the caspase inhibitors zDEVD and zVAD as well as by expression of CrmA. Vav1 is cleaved in vivo at the evolutionary conserved caspase consensus cleavage site DLYD161C, generating the carboxy-terminal cleavage product Vav1p76 of intermediate stability. In vitro caspase assays reveal cleavage of Vav1 at position 161 either by apoptotic cell lysates or by recombinant caspase-3. Mutation of Asp 161 to Ala leads to the usage of the adjacent alternative cleavage sequence DQID150D. Mutation of both cleavage sites at position 150 and 161 protects Vav1 from caspase-mediated proteolysis in vitro and in vivo. The cleavage product Vav1p76 is capable of activating JNK in T-cells, but fails to induce the phosphorylation of p38/HOG1. Vav1p76 displays a diminished capacity to activate the transcription factors NF-AT, AP-1 and NF-kappaB, and thus completely fails to activate IL-2 transcription. Since Vav1 is essential for IL-2 production and plays a central role for cytoskeletal reorganization, its proteolytic inactivation during apoptosis affects multiple downstream targets.
...
PMID:Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription. 1071 3

Growth factor deprivation-induced apoptosis plays an important role in several cellular systems. However, knowledge of the molecular mechanisms involved are restricted to a few murine models or tumor cell lines. Therefore, we aimed studying signaling pathways leading to apoptosis in activated human peripheral T cells after IL-2 withdrawal. Lymphoblasts from patients with CD 95 (Fas/APO-1)-deficiency revealed that functional CD95 was not required to induce apoptosis after IL-2 withdrawal. Moreover, apoptosis induction in response to various cytotoxic stimuli was found to be mediated in the absence of functional CD95 but was affirmatorily influenced by IL-2 signaling. Immunoblots showed no downregulation of Bcl-2 or Bcl-xL and no upregulation of Bax, whereas decreased mitochondrial membrane potential was readily measurable 24 h after cytokine deprivation. Tetrapeptide inhibitors showed limited efficacy in preventing apoptosis whereas the caspase inhibitor zVAD-FMK potently blocked induction of apoptosis. Cleavage of different fluorogenic substrates revealed multiple caspase enzyme activities in lymphoblasts, which were not negatively affected by the fas mutation. Starting at 8 h after IL-2 withdrawal, upregulation of active caspase-3 but not of caspase-8 could be detected. Taken together, our data argue for molecular mechanisms of cytokine deprivation-induced apoptosis in activated human lymphocytes independent of CD95.
...
PMID:CD 95-independent mechanisms of IL-2 deprivation-induced apoptosis in activated human lymphocytes. 1082 77

In order to effectively use cynomolgus monkeys as animal models for human diseases, more than 300 anti-human monoclonal antibodies (mAbs) were studied as to their cross-reaction with various antigens from cynomolgus monkeys (Macaca fascicularis). Two hundred twenty-nine of 339 (67.55%) anti-human mAbs that react with human antigens of CD-defined molecules, chemokine receptors, and T cell receptors were cross-reactive with the monkey antigens. Using the cross-reactive antibodies and the fluorescenced beads for calibration, the procedure for the absolute count of monkey lymphocyte subsets was developed and the mean values for CD4+ and CD8+ lymphocyte subsets in peripheral blood were 718 and 573/mm3, respectively. Moreover, intracellular cytokines, IL-2, IL-4 and IFN gamma, and intracellular apoptosis-related proteins, Bcl-2, FADD and active form of caspase-3 could be detected in peripheral blood mononuclear cells as well as various tissue cells. It is therefore practicable to detail the phenotype of leukocytes, assess the production of intracellular cytokines and enumerate T-lymphocyte subsets by using the cross-reactive human antibodies with respective antigens of cynomolgus monkeys.
...
PMID:Upgrading of flow cytometric analysis for absolute counts, cytokines and other antigenic molecules of cynomolgus monkeys (Macaca fascicularis) by using anti-human cross-reactive antibodies. 1088 48

Immunotoxins (ITs) containing plant or bacterial toxins have a dose-limiting toxicity of vascular leak syndrome (VLS) in humans. The active A chain of ricin toxin (RTA), other toxins, ribosome-inactivating proteins, and the VLS-inducing cytokine IL-2 contain the conserved sequence motif (x)D(y) where x = L, I, G, or V and y = V, L, or S. RTA-derived LDV-containing peptides attached to a monoclonal antibody, RFB4, induce endothelial cell (EC) damage in vitro and vascular leak in two animal models in vivo. We have now investigated the mechanism(s) by which this occurs and have found that (1) the exposed D75 in the LDV sequence in RTA and the C-terminal flanking threonine play critical roles in the ability of RFB4-conjugated RTA peptide to bind to and damage ECs and (2) the LDV sequence in RTA induces early manifestations of apoptosis in HUVECs by activating caspase-3. These data suggest that RTA-mediated inhibition of protein synthesis (due to its active site) and apoptosis (due to LDV) may be mediated by different portions of the RTA molecule. These results suggest that ITs prepared with RTA mutants containing alterations in LDVT may kill tumor cells in vivo in the absence of EC-mediated VLS.
...
PMID:The effect of a monoclonal antibody coupled to ricin A chain-derived peptides on endothelial cells in vitro: insights into toxin-mediated vascular damage. 1089 93

Captopril is an orally active inhibitor of angiotensin-converting enzyme (ACE) which is widely used as an anti-hypertensive agent. In addition to its ability to reduce blood pressure, captopril has a number of other biological activities. Recently the drug was shown to inhibit Fas-induced apoptosis in human activated peripheral T cells and human lung epithelial cells. In this study, we investigated whether captopril blocks activation-induced apoptosis in murine T cell hybridomas, and found that captopril inhibited IL-2 synthesis and apoptotic cell death upon activation with anti-CD3 antibody. In addition, captopril inhibited an inducible caspase-3-like activity during activation-induced apoptosis. On the other hand, captopril did not interfere with Fas signalling, since anti-Fas antibody-induced apoptosis in Fas+ Jurkat cells was unaffected by the drug. Furthermore, we examined whether captopril blocks activation-induced apoptosis by interfering with expression of Fas, Fas ligand (FasL), or both on T cell hybridomas. FasL expression on activated T cells was significantly inhibited by captopril, whereas up-expression of Fas was partially inhibited, as assessed by cell surface staining. Taking all data together, we conclude that captopril prevents activation-induced apoptosis in T cell hybridomas by interfering with T cell activation signals. Captopril has been reported to induce systemic lupus erythematosus syndrome, and our findings may be useful for elucidating the mechanism of captopril-induced autoimmunity.
...
PMID:Angiotensin-converting enzyme inhibitor captopril prevents activation-induced apoptosis by interfering with T cell activation signals. 1097 19

Degeneration of the dopamine (DA) neurons of the substantia nigra pars compacta and the resulting loss of nerve terminals accompanied by DA deficiency in the striatum are responsible for most of the movement disturbances called parkinsonism, observed in Parkinson's disease (PD). One hypothesis of the cause of degeneration of the nigrostriatal DA neurons is that PD is caused by programmed cell death (apoptosis) due to increased levels of cytokines and/or decreased ones of neurotrophins. We and other workers found markedly increased levels of cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-2, IL-4, IL-6, transforming growth factor (TFG)-alpha, TGF-beta1, and TGF-beta2, and decreased ones of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), in the nigrostriatal DA regions and ventricular and lumbar cerebrospinal fluid of PD patients. Furthermore, the levels of TNF-alpha receptor R1 (TNF-R1, p55), bcl-2, soluble Fas (sFas), and the activities of caspase-1 and caspase-3 were also elevated in the nigrostriatal DA regions in PD. In experimental animal models of PD, IL-1beta level was increased and NGF one decreased in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice, and TNF-alpha level was increased in the substantia nigra and striatum of the 6-hydroxydopamine (6OHDA)-injected side of hemiparkinsonian rats. L-DOPA alone or together with 6OHDA does not increase the level of TNF-alpha in the brain in vivo. Increased levels of proinflammatory cytokines, cytokine receptors and caspase activities, and reduced levels of neurotrophins in the nigrostriatal region in PD patients, and in MPTP- and 6OHDA-produced parkinsonian animals suggest increased immune reactivity and programmed cell death (apoptosis) of neuronal and/or glial cells. These data indicate the presence of such proapoptotic environment in the substantia nigra in PD that may induce increased vulnerability of neuronal or glial cells towards a variety of neurotoxic factors. The probable causative linkage among the increased levels of proinflammatory cytokines and the decreased levels of neurotrophins, candidate parkinsonism-producing neurotoxins such as isoquinoline neurotoxins (Review; Nagatsu, 1997), and the genetic susceptibility to toxic factors, remains for further investigation in the molecular mechanism of PD. The increased cytokine levels, decreased neurotrophin ones, and the possible immune response in the nigrostriatal region in PD indicate new neuroprotective therapy including nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, immunosuppressive or immunophilin-binding drugs such as FK-506, and drugs increasing neurotrophins.
...
PMID:Changes in cytokines and neurotrophins in Parkinson's disease. 1120 47

1 2 3 4 5 6 7 8 9 10 Next >>