Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The temperature-sensitive murine p53val135 mutant was introduced into 3 human malignant glioma cell lines to examine the effects of the p53 status on BCL-2 family protein expression, CD95 expression, and sensitivity to CD95 ligand (CD95L)-induced apoptosis. p53val135 behaves as a dominant negative mutant at 38.5 degrees C but assumes p53 wild-type properties. In order to dissect (i) specific effects of wild-type versus mutant p53, and (ii) transdominant-negative versus gain-of-function effects of mutant p53, we included glioma cell lines with functional wild-type (LN-229), mutant (LN-18) or deleted (LN-308) p53 genes. Wild-type, but not mutant, p53val135 promoted G2/M arrest and accumulation of BAK protein in all cell lines. The levels of other BCL-2 family members including BAX, BCL-2, BCL-X or MCL-1 were not consistently modulated by mutant or wild-type p53val135. Wild-type, but not mutant, p53val135 enhanced CD95 expression in all cell lines. CD95L-evoked caspase 3 activity was unaffected by wild-type p53 in all cell lines. Unexpectedly, mutant p53val135 differentially modulated caspase 3 activity in a gain-of-function fashion in that caspase 3 activity induced by CD95L was enhanced in LN-229 and LN-308 cells but reduced in LN-18 cells. Yet, mutant p53val135 enhanced the sensitivity to CD95L in LN-18 cells, had no effect in LN-229 cells, and decreased the sensitivity of LN-308 cells. Corresponding to the unaltered CD95L-evoked caspase 3 activity, wild-type p53val135 had no major effect on CD95L-induced apoptosis, except for a moderate sensitization of LN-229 cells but only when protein synthesis was inhibited. Thus, wild-type p53 induces BAK and CD95 expression in human glioma cells without enhancing their susceptibility to CD95-mediated apoptosis, and mutant p53 modulates CD95L-evoked apoptotic signalling in a gain-of-function fashion up-stream and down-stream of caspase 3 activation.
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PMID:p53 enhances BAK and CD95 expression in human malignant glioma cells but does not enhance CD95L-induced apoptosis. 1035 42

UVB-induced DNA damage is a crucial event in UVB-mediated apoptosis. On the other hand, UVB directly activates death receptors on the cell surface including CD95, implying that UVB-induced apoptosis can be initiated at the cell membrane through death receptor clustering. This study was performed to measure the relative contribution of nuclear and membrane effects in UVB-induced apoptosis of the human epithelial cell line HeLa. UVB-mediated DNA damage can be reduced by treating cells with liposomes containing the repair enzyme photolyase followed by exposure to photoreactivating light. Addition of photolyase followed by photoreactivation after UVB reduced the apoptosis rate significantly, whereas empty liposomes had no effect. Likewise, photoreactivating treatment did not affect apoptosis induced by the ligand of CD95, CD95L. UVB exposure at 4 degrees C, which prevents CD95 clustering, also reduced the apoptosis rate, but to a lesser extent. When cells were exposed to UVB at 4 degrees C and treated with photolyase plus photoreactivating light, UVB-induced apoptosis was almost completely prevented. Inhibition of caspase-3, a downstream protease in the CD95 signaling pathway, blocked both CD95L and UVB-induced apoptosis, whereas blockage of caspase-8, the most proximal caspase, inhibited CD95L-mediated apoptosis completely, but UVB-induced apoptosis only partially. Although according to these data nuclear effects seem to be slightly more effective in mediating UVB-induced apoptosis than membrane events, both are necessary for the complete apoptotic response. Thus, this study shows that nuclear and membrane effects are not mutually exclusive and that both components contribute independently to a complete response to UVB.
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PMID:Nuclear and cell membrane effects contribute independently to the induction of apoptosis in human cells exposed to UVB radiation. 1039 32

T-cell apoptosis is a mechanism regulating T-cell homeostasis. Activation renders T cells susceptible to activation-induced cell death, a process mediated through CD95 ligand/CD95 (Apo-1/Fas) ligation. The aim of this study was to test whether antigen-presenting cells can inhibit CD95/Fas-triggered activation-induced cell death. Dendritic cells (DC), which are highly effective antigen-presenting cells, were generated in vitro from human peripheral blood monocytes by culture in granulocyte-macrophage colony-stimulating factor and interleukin 4. Subsequently, DC were cocultured with activated T cells and the effect of DC on CD95/Fas-mediated apoptosis was determined. Coculture with increasing amounts of DC prevented CD95/Fas-triggered apoptosis in a dose-dependent fashion by inhibiting activation of caspase 8 and caspase 3. This protective effect of the DC on T-cell death could be blocked by 50% by adding an anti-CD58 antibody, whereas further addition of anti-CD80 (B7.1) and anti-CD86 (B7.2) led to an even more pronounced effect. Our findings suggest that DC can protect T cells from activation-induced cell death, with CD58 ligation playing a key role.
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PMID:CD95/Fas-triggered apoptosis of activated T lymphocytes is prevented by dendritic cells through a CD58-dependent mechanism. 1048 Apr 31

Fas ligand (CD95L) and tumor necrosis factor-alpha (TNF-alpha) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two systems is involved in several forms of liver injury. Although the broad antiapoptotic action of Bcl-2 and Bcl-xL has been clearly established in various apoptotic pathways, their ability to inhibit the Fas/CD95- and TNF-alpha-mediated apoptotic signal has remained controversial. We have demonstrated that the expression of BCL-2 in hepatocytes protects them against Fas-induced fulminant hepatitis in transgenic mice. The present study shows that transgenic mice overexpressing BCL-XL in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were protective without any change in the level of endogenous Bcl-xL or Bax and inhibited hepatic caspase-3-like activity. In vivo injection of TNF-alpha caused massive apoptosis and death only when transcription was inhibited. Under these conditions, PK-BCL-XL mice were partially protected from liver injury and death but PK-BCL-2 mice were not. A similar differential protective effect of Bcl-xL and Bcl-2 transgenes was observed when Fas/CD95 was activated and transcription blocked. These results suggest that apoptosis triggered by activation of both Fas/CD95 and TNF-alpha receptors is to some extent counteracted by the transcription-dependent protective effects, which are essential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefore, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the liver whose characterization could facilitate their use to prevent the uncontrolled apoptosis of hepatocytes.
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PMID:Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice. 1048 97

We examined the effect of paclitaxel on human osteoblastic cells Saos-2 to determine if paclitaxel can affect proliferation and apoptosis. We used a p53-negative cell line in order to mimic the loss of function frequently observed at the clinical level. Paclitaxel induced cell death in a dose- and time-dependent manner. Marked nuclear condensation and fragmentation of chromatin were observed by Hoechst 33258 stain, DNA ladder formation, electron microscopy, and flow cytometry at concentrations as low as 100 nM, a concentration which can be achieved by infusion in human plasma. At 100 nM, paclitaxel induced a G2 arrest at 8 h of treatment. The cells then continued to accumulate in G2 until 72 h when the percentage of apoptotic events reached 54%. At the molecular level, Bcl-2 protein was phosphorylated at 16 h and PARP protein was cleaved, indicating the activation of caspase-3-like proteases. Caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK rescued Saos-2 cells from paclitaxel-induced apoptosis. CD95 expression was constantly high, while CD95L showed a threefold increase in expression. This suggests that, following the G2 arrest, apoptosis is induced through the CD95/CD95L system.
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PMID:Paclitaxel induces apoptosis in Saos-2 cells with CD95L upregulation and Bcl-2 phosphorylation. 1050 6

CD4 cross-linking by HIV gp120 triggers CD4+ T cell death. Several authors have suggested that this effect is mediated by CD95, but this possibility is debated by other authors. In a previous work, we found by co-capping that gp120(451) and gp120MN, but not gp120(IIIB), induce lateral association of CD4 with CD95 on the T cell surface. In this work, we used fluorescence resonance energy transfer to confirm that CD4/CD95 lateral association is induced by gp120(451), but not gp120(IIIB). Moreover, we found that gp120 ability to induce the CD4/CD95 association correlates with ability to induce cell death, since gp120(451) and gp120MN induced higher levels of cell death than did gp120(IIIB) in PHA-derived CD4+ T cell lines. CD95 involvement in gp120-induced cell death was confirmed by showing that gp120(451) and gp120MN did not induce death in CD4+ T cells derived from patients with autoimmune/lymphoproliferative disease (ALD) and decreased CD95 function. Cell death induced by gp120MN was inhibited by a recombinant CD95/IgG.Fc molecule blocking the CD95/CD95L interaction. However, inhibition was late and only partial. These data suggest that the gp120-induced CD4/CD95 association exerts a dual effect: an early effect that is independent of CD95L and may be due to direct triggering of CD95 by gp120, and a late effect that may be due to sensitization of CD95 to triggering by CD95L. In line with the former effect, cell treatment with gp120MN activated caspase 3 in the presence of Fas/IgG.Fc, which shows that cell death induced by gp120MN independently of CD95L uses the same pathway as CD95.
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PMID:The cell death-inducing ability of glycoprotein 120 from different HIV strains correlates with their ability to induce CD4 lateral association with CD95 on CD4+ T cells. 1050 74

MHC class II molecules have a crucial role in thymic selection and in generating Ag-specific T cell responses. There is extensive evidence for second messenger generation via MHC class II molecules, which can lead to apoptosis of B lymphocytes. We have examined HLA class II-mediated apoptosis in both normal and tumoral human B lymphocytes. Phosphatidylserine exposure and DNA fragmentation were observed in B cells within 24 h of stimulation via HLA class II. In marked comparison with Fas, the cell-permeable and irreversible caspase inhibitors zVAD-fmk and DEVD-fmk failed to inhibit HLA-DR-mediated apoptosis. No direct activation of caspase 3 was detected, and cleavage of pro-caspase 3 was not observed. Cleavage of poly(ADP-ribose) polymerase was detected via Fas but not via HLA class II. Although phosphatidylinositol-3-kinase has been implicated in HLA class I-mediated apoptosis, neither wortmannin nor LY294002 affected HLA class II-mediated apoptosis. CD95-sensitive cells were used to reveal that death occurred independently of CD95-CD95 ligand interactions. Overall, these data reveal a pathway of HLA-DR-mediated apoptosis that neither requires nor involves caspases. Moreover, it is phosphatidylinositol-3-kinase independent and Fas/CD95 independent. This pathway of HLA class II-mediated apoptosis could have an important role in the regulation of APC populations or in the control of malignant B lymphocyte proliferations.
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PMID:A caspase-independent pathway of MHC class II antigen-mediated apoptosis of human B lymphocytes. 1051 Mar 46

We have previously shown that nitric oxide (NO) induces apoptosis in different human neoplastic lymphoid cells through caspase activation. Here we studied the NO-mediated apoptosis in human breast cancer cell lines derived from primary tumor (BT-20) or from metastasis (MCF-7). NO donor glycerol trinitrate (GTN) induced apoptosis in both cell lines which was completely abrogated after pretreatment with the broad spectrum caspase inhibitor zVAD-fmk. NO triggered also a time-dependent activation of caspase-1, caspase-3, and caspase-6 in these cells. Moreover, NO caused a release of mitochondrial protein cytochrome c into the cytosol, an increase in the number of cells with low mitochondrial transmembrane potential and with high level of reactive oxygen species production. However, NO did not induce mRNA expression of CD95 (APO-1/Fas) ligand. FAS-associated phosphatase-1 (FAP-1) molecule was constitutively expressed at the mRNA level and did not show any changes upon NO treatment in both breast cancer cell lines. The expression of the pro-apoptotic protein Bax and of the anti-apoptotic protein Bcl-2 remained unchanged in MCF-7 and BT-20 cells upon GTN treatment. We suggest that the mechanism of NO-mediated activation of the caspase cascade and subsequent apoptosis in human breast cancer cells required mitochondrial damage (in particular, cytochrome c release, disruption of mitochondrial transmembrane potential and generation of reactive oxygen species) but not the activation of the CD95/CD95L pathway.
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PMID:Nitric oxide-mediated apoptosis in human breast cancer cells requires changes in mitochondrial functions and is independent of CD95 (APO-1/Fas). 1060 55

Activation-induced cell death (AICD) in T cells is mediated by CD95 ligand (CD95L)/receptor interaction, which has also been implicated in apoptosis induction by some anticancer agents. In this article we show that both anti-CD3-triggering (AICD) and doxorubicin treatment led to the production of a functionally active CD95L in the CD3+/T-cell receptor-positive (TCR+) T leukemia cell line H9. CD95L-expressing H9 cells killed CD95-sensitive J16 or CEM target cells, but not CD95-resistant CEM or J16 cells overexpressing dominant negative FADD (J16/FADD-DN). By immunoprecipitation, CD95L was physically bound to CD95, suggesting that AICD and doxorubicin-induced apoptosis involve CD95L-mediated CD95 aggregation, thereby triggering the CD95 death pathway. CD95 aggregation was associated with the recruitment of FADD and caspase-8 to the CD95 receptor to form the CD95 death-inducing signaling complex (DISC), resulting in caspase-8 activation and cleavage of the effector caspase-3 and PARP. Blocking of the CD95L/receptor interaction by antagonistic antibodies to CD95 or to CD95L also blocked AICD and inhibited the early phase of doxorubicin-induced apoptosis, though cell death induced by doxorubicin eventually proceeded in a CD95-independent manner. These findings may explain some conflicting data on the role of death receptor systems in drug-induced apoptosis. Thus, in cells with an inducible CD95 receptor/ligand system, drug-induced apoptosis may be mediated by CD95L-initiated DISC formation and activation of downstream effector programs similar to AICD in T cells. (Blood. 2000;95:301-308)
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PMID:Functional CD95 ligand and CD95 death-inducing signaling complex in activation-induced cell death and doxorubicin-induced apoptosis in leukemic T cells. 1060 16

We compared the expression of cell adhesion molecules (CAMs), cytotoxic granule proteins, and apoptosis-related proteins by immunohistology and in situ terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick end labeling (TUNEL) of 10 cases of cutaneous CD56+ NK/T cell lymphoma with and 6 cases without angiodestruction. Lymphoma cells in cases with angiodestruction frequently expressed CAMs CD2, CD11a, and CD49d and their ligands CD58, CD54, and CD106 and were positive for CD122 and cytotoxic granule proteins TIA1, perforin, and granzyme B. Lymphoma cells in cases without angiodestruction mostly were negative for CD2, CD58, CD54, CD106, and TIA1 and weakly positive for perforin and granzyme B. In the TUNEL method, mean apoptotic indices (AI) for cases with angiodestruction showed a higher percentage than those without angiodestruction. CD95L, CD95, apoptosis-induced cysteine protease CPP32, apoptosis-promoting protein Bax, and proliferating marker (MIB1) frequently were positive in the lymphoma cells of cases with angiodestruction, but there was no expression of apoptosis-inhibitor protein Bcl2. In most cases without angiodestruction, lymphoma cells were positive for CD95L and Bax and negative for CD95, CPP32, and MIB1. CAMs and the 3 cytotoxic granule proteins and an apoptosis pathway might be important factors in the paracrine and autocrine mechanisms of tissue necrosis in cutaneous CD56+ NK/T cell lymphoma.
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PMID:Angiodestruction and tissue necrosis of skin-involving CD56+ NK/T-cell lymphoma are influenced by expression of cell adhesion molecules and cytotoxic granule and apoptosis-related proteins. 1066 22


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