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)

Phosphatidylserine exposure in the exoplasmic leaflet of the plasma membrane is one of the early hallmarks of cells undergoing apoptosis. The shedding of membrane particles carrying Ags testifying to their tissue origin is another characteristic feature. Annexin V, a protein of as yet unknown specific physiologic function, presents a high Ca2+-dependent affinity for phosphatidylserine and forms two-dimensional arrays at the membrane surface. In this study, we report the delaying action of annexin V on apoptosis in the CEM human T cell line expressing CD4 and the normal cellular prion protein (PrPc), two Ags of particular relevance to cell degeneration and with different attachments to the membrane. The effect of annexin V was additive to that of z-Val-Ala-Asp-fluoromethyl ketone, a potent caspase inhibitor. Annexin V significantly reduced the degree of proteolytic activation of caspase-3, and totally blocked the release of CD4+ and PrPc+ membrane particles. z-Val-Ala-Asp-fluoromethyl ketone was a more powerful antagonist of caspase-3 processing, but prevented the shedding of CD4+ vesicles only partially and had no effect on that of PrPc+ ones. These results suggest that an external membrane constraint, such as that exerted by annexin V, has important consequences on the course of programmed cell death and on the dissemination of particular Ags. In vivo, annexin V had a significant protective effect against spleen weight loss in mice treated by an alkylating agent previously shown to induce lymphocyte apoptosis.
 ...
PMID:Annexin V delays apoptosis while exerting an external constraint preventing the release of CD4+ and PrPc+ membrane particles in a human T lymphocyte model. 1022 3

Recent work from this laboratory demonstrated potent inhibition of apoptosis in human alveolar epithelial cells (AECs) by the angiotensin-converting enzyme inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 (Lung Cell. Mol. Physiol. 19): L1013-L1017, 1998]. On this basis, we hypothesized that apoptosis in this cell type might be induced by angiotensin II (ANG II) through its interaction with the ANG II receptor. Purified ANG II induced dose-dependent apoptosis in both the human AEC-derived A549 cell line and in primary type II pneumocytes isolated from adult Wistar rats as detected by nuclear and chromatin morphology, caspase-3 activity, and increased binding of annexin V. Apoptosis also was induced in primary rat AECs by purified angiotensinogen. The nonselective ANG II-receptor antagonist saralasin completely abrogated both ANG II- and angiotensinogen-induced apoptosis at a concentration of 50 microgram/ml. With RT-PCR, both cell types expressed the ANG II-receptor subtypes 1 and 2 and angiotensin-converting enzyme (ACE). The nonthiol ACE inhibitor lisinopril blocked apoptosis induced by angiotensinogen, but not apoptosis induced by purified ANG II. These data demonstrate the presence of a functional ANG II-dependent pathway for apoptosis in human and rat AECs and suggest a role for the ANG II receptor and ACE in the induction of AEC apoptosis in vivo.
 ...
PMID:Angiotensin II induces apoptosis in human and rat alveolar epithelial cells. 1033 45

We have investigated the possibility of the involvement of PARP in apoptosis, independently of its enzymatic activity. We thus transfected PARP(-)/(-)A11 cells with a DNA construct encoding the PARP DNA-binding domain (DBD) fragment or mutants DBDbd(-), defective in DNA binding to DNA strand breaks, and DBDcl(-), resistant to caspase-3 cleavage. We found that in the absence of PARP, while expression of DBD has only a marginal effect, expression of the mutants strongly inhibits the apoptosis induced by staurosporine, as measured by the binding of annexin V. Moreover, the mutants, but not DBD, inhibit the cleavage of DNA PKcs, suggesting inhibition of activation of caspase-3. In addition, the mutant transfectants are fractionally less susceptible to low doses of an alkylating agent than the DBD transfectant or the original A11 line. The results suggest that the DBD fragment of PARP, apart from its classical role of nick detection and DNA binding, participates in complexes involved in upstream events leading to activation of the caspase cascade.
 ...
PMID:Inhibition of apoptosis of a PARP(-)/(-)cell line transfected with PARP DNA-binding domain mutants. 1043 94

The induction of apoptosis in T cells is one of several mechanisms by which tumors escape immune recognition. We have investigated whether tumors induce apoptosis in dendritic cells (DC) by co-culture of murine or human DC with different tumor cell lines for 4-48 h. Analysis of DC morphological features, JAM assay, TUNEL, caspase-3-like and transglutaminase activity, Annexin V binding, and DNA fragmentation assays revealed a time- and dose-dependent induction of apoptosis in DC by tumor-derived factors. This finding is both effector and target specific. The mechanism of tumor-induced DC apoptosis involved regulation of Bcl-2 and Bax expression. Double staining of both murine and human tumor tissues confirmed that tumor-associated DC undergo apoptotic death in vivo. DC isolated from tumor tissue showed significantly higher levels of apoptosis as determined by TUNEL assay when compared with DC isolated from spleen. These findings demonstrate that tumors induce apoptosis in DC and suggest a new mechanism of tumor escape from immune recognition. DC protection from apoptosis will lead to improvement of DC-based immunotherapies for cancer and other immune diseases.
 ...
PMID:Tumor's other immune targets: dendritic cells. 1044 78

The induction of cell death by aspirin was analysed in HT-29 colon carcinoma cells. Aspirin induced two hallmarks of apoptosis: nuclear chromatin condensation and increase in phosphatidylserine externalization. However, aspirin did not induce either oligonucleosomal fragmentation of DNA, decrease in DNA content or nuclear fragmentation. The effect of aspirin on Annexin V binding was inhibited by the caspase inhibitor Z-VAD.fmk, indicating the involvement of caspases in the apoptotic action of aspirin. However, aspirin did not induce proteolysis of PARP, suggesting that aspirin does not increase nuclear caspase 3-like activity in HT-29 cells. This finding may be related with the 'atypical' features of aspirin-induced apoptosis in HT-29 cells.
 ...
PMID:Aspirin induces cell death and caspase-dependent phosphatidylserine externalization in HT-29 human colon adenocarcinoma cells. 1049 55

Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, using leukemic cell lines, time course of cytarabine-induced apoptosis was examined morphologically, using annexin V method, TUNEL method and fluorometric assay for caspase-3 activity. Morphological changes characteristic of apoptosis were observed in U937 and HL60 cells after 4-hour incubation with cytarabine and progressively evident until 48-hour incubation, but rarely found in K562 cells. In annexin V method and assay for caspase-3 activity, changes accompanied by apoptosis could also be detected at 4-hour incubation with cytarabine, but in TUNEL method, they were not found until 24-hour incubation. The advantage of annexin V method which detects phosphatidylserine emerging on cell surface during the early course of apoptosis included simplicity and rapidity of the procedure and short time requirement for apoptosis to appear after incubation with cytarabine. Usefulness of annexin V method in a study of clinical samples was discussed.
 ...
PMID:[Evaluation of cytarabine-induced apoptosis in leukemic cell lines; utility of annexin V method]. 1051 10

We have previously shown that when annexin V is present during the execution of a cell death program, apoptosis is delayed. This is reflected by the inhibition of DNA cleavage and of the release of apoptotic membrane particles, and by reduction of the proteolytic processing of caspase-3. Here, we have studied the mechanism(s) through which annexin V counteracts apoptosis in the human CEM T cell line. The degree of apoptosis inhibition was associated with an increase of intracellular Ca(2+) concentration ([Ca(2+)](i)). Reduction of the extracellular Ca(2+) concentration by EGTA abolished the anti-apoptotic effect, suggesting that annexin V favors Ca(2+) influx and that Ca(2+) acts as an inhibitor rather than an activator of apoptosis in CEM T cells. The effects on apoptosis and [Ca(2+)](i) of several modified annexins with different electrophysiological properties indicate that the N-terminal domain of annexin V is necessary for the Ca(2+)-dependent anti-apoptotic action of annexin V. These results suggest that annexin V regulates membrane Ca(2+) permeability and is protective against apoptosis by increasing [Ca(2+)](i) in CEM T cells.
 ...
PMID:Annexin V counteracts apoptosis while inducing Ca(2+) influx in human lymphocytic T cells. 1060 Apr 85

We have demonstrated that a novel Ste20-related kinase, designated SLK, mediates apoptosis and actin stress fiber dissolution through distinct domains generated by caspase 3 cleavage. Overexpression of SLK in C2C12 myoblasts stimulated the disassembly of actin stress fibers and focal adhesions and induced apoptosis, as determined by annexin V binding and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling analysis. SLK was cleaved by caspase 3 in vitro and in vivo during c-Myc-, tumor necrosis factor alpha, and UV-induced apoptosis. Furthermore, cleavage of SLK released two domains with distinct activities: an activated N-terminal kinase domain that promoted apoptosis and cytoskeletal rearrangements and a C-terminus domain that disassembled actin stress fibers. Moreover, our analysis has identified a novel conserved region (termed the AT1-46 homology domain) that efficiently promotes stress fiber disassembly. Finally, transient transfection of SLK also activated the c-Jun N-terminal kinase signaling pathway. Our results suggest that caspase-activated SLK represents a novel effector of cytoskeletal remodeling and apoptosis.
 ...
PMID:Caspase 3 cleavage of the Ste20-related kinase SLK releases and activates an apoptosis-inducing kinase domain and an actin-disassembling region. 1061 Dec 47

The MDM2 oncoprotein has been shown to inhibit p53-mediated growth arrest and apoptosis. It also confers growth advantage to different cell lines in the absence of p53. Recently, the ability of MDM2 to arrest the cell cycle of normal human fibroblasts has also been described. We report a novel function for this protein, showing that overexpression of MDM2 promotes apoptosis in p53-deficient, human medullary thyroid carcinoma cells. These cells, devoid of endogenous MDM2 protein, exhibited a significant growth retardation after stable transfection with mdm2. Cell cycle distribution of MDM2 transfectants [medullary thyroid tumor (MTT)-mdm2] revealed a fraction of the cell population in a hypodiploid status, suggesting that MDM2 is sufficient to promote apoptosis. This circumstance is further demonstrated by annexin V labeling. MDM2-induced apoptosis is partially reverted by transient transfection with p53 and p19ARF. Both MTT and MTT-mdm2 cells were tumorigenic when injected into nude mice. However, the percentage ofapoptotic nuclei in tumor sections derived from MDM2-expressing cells was significantly higher relative to that in the parental cell line. MDM2-mediated programmed cell death is at least mediated by a down-regulation of the antiapoptotic protein Bcl-2. Protein levels of caspase-2, which are undetectable in the parental cell line, appear clearly elevated in MTT-mdm2 cells. Caspase-3 activation does not participate in MDM2-induced apoptosis, as determined by protein levels or poly(ADP-ribose) polymerase fragmentation. The results observed in this medullary carcinoma cell line show for the first time that the product of the mdm2 oncogene mediates cell death by apoptosis in p53-deficient tumor cells.
 ...
PMID:The MDM2 oncoprotein promotes apoptosis in p53-deficient human medullary thyroid carcinoma cells. 1061 65

Damage to bone tissue due to heat shock is one of the main causes of the failure of osseointegration at the bone-implant interface. To investigate the effect of heat shock on regeneration of bone tissue, osteoblasts were exposed to heat shock for 10 minutes at 42, 45, or 48 degrees C or kept at 37 degrees C as a control. After 10 minutes of heat shock, disruption of actin filaments was seen in the cells and the degree of disruption increased with the temperature. The cytoskeleton reassembled after a 12-hour incubation at 37 degrees C in the cells treated at 42 or 45 degrees C, but this reversible recovery did not occur in the cells treated at 48 degrees C. Flow cytometric analysis showed that heat shock at 48 degrees C increased the number of necrotic cells to 15-20% within minutes (p < 0.05 compared with 37 degrees C). Apoptosis, evidenced by annexin V staining, DNA laddering, and caspase 3 activation, started after 6-8 hours of incubation, reached a peak at 12 hours, and gradually declined (p<0.05). Pretreatment with the antioxidant N-acetyl-L-cysteine reduced the necrosis induced at 48 degrees C of heat shock by one-half (p<0.05) but had no significant effect on caspase 3 activation induced by heat shock, suggesting that reactive oxygen species were critical in heat shock-induced necrosis but not in apoptosis. Heat shock at 48 degrees C induced a sustained translocation of p53 into the nucleus and a sustained activation of c-jun N-terminal kinase, whereas that at 42 and 45 degrees C induced only transient p53 translocation and c-jun N-terminal kinase activation. These results suggest that the sustained activation of p53 and c-jun N-terminal kinase pathways may contribute to heat shock-induced apoptosis. On the other hand, heat shock protein 70 increased dramatically in the cells treated at 45 or 48 degrees C, suggesting that the protecting mechanism in the cells was also activated. Such protection was able to prevent apoptosis in cells treated at 45 degrees C but not in those treated at 48 degrees C.
 ...
PMID:Heat shock-induced necrosis and apoptosis in osteoblasts. 1063 56


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