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)

Idiopathic acquired sideroblastic anaemias (IASAs) form a subgroup of the myelodysplastic syndromes and are characterized by mitochondrial iron accumulation, bone marrow erythroid hyperplasia and decreased peripheral red blood cell counts. Increased intramedullary apoptosis of erythroid precursors is presumed to constitute the pathophysiological mechanism explaining this ineffective erythropoiesis, but if and how mitochondrial dysfunction is implicated in this process is currently unknown. We therefore studied bone marrow precursor cells obtained from nine patients with IASA for (i) caspase 3 activity, (ii) numbers of Annexin V- and 7-amino-actinomycin-positive cells, (iii) numbers of cells with diminished mitochondrial membrane potential, Delta Psi(m), and (iv) numbers of cells producing reactive oxygen species (ROS), and we compared the results with those of five normal bone marrow samples. Compared with controls, we found increased caspase 3 activity in all IASA samples, which correlated with increased numbers of Annexin-V-positive cells (r = 0.7). Analysis of different subpopulations showed increased apoptosis in erythroid populations compared with myeloid and/or lymphoid populations in five out of nine cases, and increased apoptosis in the last two populations in four out of nine cases. As evidence of mitochondrial dysfunction, Delta Psi(m) was found to be diminished in the erythroid subpopulations of all cases of IASA (66.6 +/- 17% vs. 34.6 +/- 12% in normals). Delta Psi(m) decrease was correlated to Annexin V positivity (r = 0.7). Astonishingly, no difference was found between IASA and normal bone marrows with regard to the number of ROS-producing cells. In fact, both groups exhibited a similar low proportion of ROS production (10.3 +/- 7% in normals vs. 6.8 +/- 5% in IASA). Taken together, our results show that mitochondria are clearly implicated in the apoptotic process in IASA patients. Whether this is a result of an intramitochondrial defect (e.g. Fe accumulation, secondary to mitochondrial or nuclear DNA mutations) or is secondary to an extracellular stimulus [e.g. tumour necrosis factor (TNF), Fas ligand (FasL)] remains to be determined.
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PMID:Increased apoptosis in acquired sideroblastic anaemia. 1112 46

CD95 (Fas/Apo-1) is a transmembrane molecule that induces apoptosis and plays a central role in the regulation of the immune response. The present study describes two new B lymphoid cell lines, B593 and BR97, derived from non-Hodgkin's lymphoma, which differ in susceptibility to CD95-mediated apoptosis. While B593 cells are sensitive to CD95mediated apoptosis, BR97 cells are completely resistant. Activation of caspase-8 and caspase-3 proteases plays an important role in the CD95 signalling pathway. CD95 stimulation induced caspase-8 and caspase-3 activation in B593, but not in BR97 cells. However, activation of both caspase-8 and caspase-3 was achieved in BR97 cells treated with staurosporine. Furthermore, protein synthesis inhibition by cycloheximide restored sensitivity to CD95-mediated apoptosis and allowed activation of both caspase-8 and caspase-3 in BR97 cells. These results indicate that, in BR97 cells, both caspases are functional and suggest that CD95-apoptosis resistance may result from the presence of inhibitory factor(s). Constitutive high level expression of the apoptotic inhibitor c-FLIP was observed in the CD95-resistant BR97 cell line compared to B593. Moreover, downregulation of c-FLIP expression level by protein synthesis inhibition strictly correlated with restored sensitivity to CD95-mediated apoptosis in BR97 cells. Furthermore, we demonstrate that c-FLIP is recruited to the CD95 DISC in BR97 cells together with caspase-8 and FADD. The data presented in this study strongly suggests that, in a B-NHL-derived cell line, resistance to CD95-mediated apoptosis results from endogenous high level expression of apoptotic inhibitor c-FLIP.
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PMID:Resistance to CD95-mediated apoptosis through constitutive c-FLIP expression in a non-Hodgkin's lymphoma B cell line. 1118 5

The activation of caspase-8, a crucial upstream mediator of death receptor signaling, was investigated in epirubicin- and Taxol-induced apoptosis of B-lymphoma cells. This study was performed because the CD95/Fas receptor-ligand interaction, recruitment of the Fas-associated death domain (FADD) adaptor protein, and subsequent activation of procaspase-8 have been implicated in the execution of drug-induced apoptosis in other cell types. Indeed, active caspase-8 was readily detected after treatment of mature and immature B-lymphoid cells with epirubicin or Taxol. However, neither constitutive nor drug-induced expression of the CD95/Fas ligand was detectable in B-lymphoma cells. Furthermore, overexpression of a dominant-negative FADD mutant (FADDdn) did not block caspase-8 processing and subsequent DNA fragmentation, indicating that drug-induced caspase-8 activation was mediated by a CD95/Fas-independent mechanism. Instead, caspase-8 cleavage was slightly preceded by activation of caspase-3, suggesting that drug-induced caspase-8 activation in B-lymphoma cells is a downstream event mediated by other caspases. This assumption was confirmed in 2 experimental systems-zDEVD-fmk, a cell-permeable inhibitor of caspase-3-like activity, blocked drug-induced caspase-8 cleavage, and depletion of caspase-3 from cell extracts impaired caspase-8 cleavage after in vitro activation with dATP and cytochrome c. Thus, these data indicate that drug-induced caspase-8 activation in B-lymphoma cells is independent of death receptor signaling and is mediated by postmitochondrial caspase-3 activation.
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PMID:Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3. 1122 83

The retroviral oncoprotein v-Rel is a transcriptional activator in the Rel/NF-kappa B family. v-Rel causes rapidly fatal lymphomas in young chickens, and transforms and immortalizes chicken lymphoid cells in vitro. Several mutations that have enhanced the oncogenicity of v-Rel have been selected during in vitro and in vivo passage of v-Rel-containing retroviruses. In this report, we show that the C-terminal deletion and two point mutations (Asp-->Gly at residue 91 and Asp-->Asn at residue 437) in v-Rel make it resistant to cleavage by the cell-death protease caspase-3. In contrast, c-Rel, which has Asp residues at these sites, can be cleaved by caspase-3 in vitro as well as in vivo in cells induced to undergo apoptosis. We have characterized activities of v-Rel mutants with recreated single caspase-3 cleavage sites, two cleavage sites, or an introduced artificial cleavage site. All of these mutant v-Rel proteins are sensitive to caspase-3 cleavage in vitro, and show wild-type activity in terms of nuclear localization in chicken fibroblasts and DNA binding in vitro. Moreover, all caspase-3-sensitive v-Rel mutants transform chicken spleen cells in vitro and induce fatal lymphoid tumors in vivo to approximately the same extent as wild-type v-Rel. As with v-Rel mutants, caspase-3-resistant c-Rel mutants behave similarly to caspase-3-sensitive wild-type c-Rel in terms of DNA binding, transcriptional activation, in vitro transformation, and tumorigenicity. Mammalian c-Rel proteins can also be cleaved by caspase-3 in vitro, and a c-Rel mutant from a human pre-T lymphoma cell line is less sensitive than wild-type human c-Rel to cleavage by caspase-3. Taken together, these results demonstrate that specific mutations render oncogenic forms of Rel proteins resistant to cleavage by a cell-death caspase; however, the biological relevance of this resistance remains unclear. Nevertheless, to our knowledge, this is the first demonstration of mutations in caspase-3 recognition sites occurring during the evolution of an oncogenic protein.
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PMID:Three mutations in v-Rel render it resistant to cleavage by cell-death protease caspase-3. 1128 19

We have reported previously that beta2-microglobulin (beta2m) induces apoptosis in leukemic cells in vitro, and that an interaction between beta2m and HLA class I antigen induces apoptosis. Here we examined whether beta2m can induce apoptosis in leukemic cells in vivo and whether it has an antitumor effect in tumor-bearing mice. Daily administration of 50 or 250 microg of beta2m induced apoptosis and an antitumor effect on K562 leukemia cell-bearing mice in the same manner as tumor necrosis factor-alpha. In tumor tissues in beta2m-treated mice, both caspase-3 and nuclear factor-kappaB (NF-kappaB) were stained more strongly than in control mice by anti-caspase-3 and anti-NF-kappaB p65/Rel A polyclonal antibodies. We also observed the in vivo immunological effects of beta2m on lymphoid and hematopoietic organs, such as thymus, bone marrow, Peyer's patches, liver, and spleen in normal mice. Using antibodies against caspase-3 and NF-kappaB, immunohistochemical staining showed that no specific tissues were damaged or stained in normal mice. We conclude that beta2m stimulates caspase-3 and NF-kappaB pathways to induce apoptosis, making it a useful approach to a new therapy for leukemia.
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PMID:Antitumor effect of beta2-microglobulin in leukemic cell-bearing mice via apoptosis-inducing activity: activation of caspase-3 and nuclear factor-kappaB. 1138 69

The balance between cell survival and cell death is critical for normal lymphoid development. This balance is maintained by signals through lymphocyte antigen receptors and death receptors such as CD95/Fas. In some cells, ligating the B cell antigen receptor can protect the cell from apoptosis induced by CD95. Here we report that ligation of CD95 inhibits antigen receptor-mediated signaling. Pretreating CD40-stimulated tonsillar B cells with anti-CD95 abolished B cell antigen receptor-mediated calcium mobilization. Furthermore, CD95 ligation led to the caspase-dependent inhibition of antigen receptor-induced calcium mobilization and to the activation of mitogen-activated protein kinase pathways in B and T cell lines. A target of CD95-mediated caspase 3-like activity early in the apoptotic process is the adaptor protein GrpL/Gads. GrpL constitutively interacts with SLP-76 via its C-terminal SH3 domain to regulate transcription factors such as NF-AT. Cleavage of GrpL removes the C-terminal SH3 domain so that it is no longer capable of recruiting SLP-76 to the membrane. Transfection of a truncated form of GrpL into Jurkat T cells blocked T cell antigen receptor-induced activation of NF-AT. These results suggest that CD95 signaling can desensitize antigen receptors, in part via cleavage of the GrpL adaptor.
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PMID:CD95/Fas induces cleavage of the GrpL/Gads adaptor and desensitization of antigen receptor signaling. 1139 Oct

The role of Bcl-2 in TRAIL-induced apoptosis has been investigated in lymphoid cells. Here we show that the human prostatic carcinoma cell line PC3 was sensitive to TRAIL treatment whereas PC3 overexpressing of Bcl-2 was resistant. TRAIL receptors ligation in PC3 activated caspases -2, -3, -7, -8, and -9, induced Bid processing, dissipation of mitochondrial transmembrane potential (Delta Psi(m)), and cytochrome c release. We have detected caspases -8 and -3 only in the cytosolic fraction of cells, but caspases -2, -7, and -9 were found both in cytosolic and mitochondrial fractions. Bcl-2 overexpression did not affect caspase-8 activation although it did change the processing pattern of caspase-3. At the same time, Bcl-2 overexpression inhibited the activation of mitochondrial localized caspases -2, -7, and -9. Bcl-2 also abrogated TRAIL-induced cytochrome c release and dissipation of Delta Psi(m). These findings suggest that TRAIL-induced apoptosis in the epithelial cell line PC3 depends both on mitochondrial integrity and caspase activation.
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PMID:Bcl-2 oncoprotein protects the human prostatic carcinoma cell line PC3 from TRAIL-mediated apoptosis. 1142 Jun 95

Clathrin-mediated vesicle formation is an essential step in the intracellular trafficking of the protein and lipid. Binding of clathrin assembly protein to clathrin triskelia induces their assembly into clathrin-coated vesicles (CCVs). In order to better understand a possible role of post-translational modification of CALM (clathrin assembly protein lymphoid myeloid), the homologue of AP180, in the assembly of CCVs, CALM was expressed in the cell-free reticulocyte translation system that is capable of carrying out post-translational modification. The apparent molecular weight of the expressed recombinant CALM was estimated as 105 kD. Alkaline phosphatase treatment of CALM resulted in a mobility shift on SDS-PAGE. We found that CALM was associated with the proteins harboring SH3 domain, promote assembly of clathrin triskelia into clathrin cage and bound to the preformed clathrin cage. CALM was also proteolyzed by caspase 3 and calpain but not by caspase 8. These results indicated that the post-translationally modified CALM, expressed in the eukaryotic cell-free reticulocyte translation system was able to mediate the assembly of clathrin and the coated-vesicle formation.
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PMID:Cell-free expression and functional reconstitution of CALM in clathrin assembly. 1146 Aug 87

This study evaluated whether the feeding of rats with a 15% orange-pulp diet affects the lymphatic system and the tumorigenic response in rats exposed to a high dose of carcinogen. Five-week-old Sprague Dawley rats were divided into 2 groups fed a control chow diet or the same diet with 15% orange pulp. All rats were injected with 1,2-dimethylhydrazine (DMH) (20 mg/kg) weekly for 6 weeks. At 8 months, tumors, spleens and descending colon were taken from each group for analyses. Feeding rats the 15% orange-pulp diet did not reduce the tumor number but modified the number of adenocarcinomas found in the orange-pulp group compared to controls: 66.7% vs. 93.7%. The number of endophytic tumors was also significantly lower in the experimental group: 6.3% vs. 32.3% in controls. DMH affected the size of the splenic structures. The size of follicles and germinal centers decreased significantly in tumor-bearing rats compared to tumor-free rats. This effect was changed in rats fed the orange-pulp diet. In tumor-bearing rats from this group, only the area of the marginal zone decreased and the red pulp increased compared to tumor-free rats. The size of germinal centers significantly increased compared to tumor-bearing rats in controls. The total number of lymphoid cells decreased in germinal centers of spleens obtained from control tumor-bearing rats compared to tumor-free rats. DMH alone significantly increased the total number of cells in the colon mucosa of the rats fed the control diet. In tumor-bearing rats exposed to the carcinogen and fed the 15% orange-pulp diet, the total number of cells and the number of Ki-67+ cells increased in the depth of tumors whereas the number of CD8+ T cells increased in the colon mucosa, at the border of tumors and its depth. The caspase-3 protein a cysteine protease was elevated in tumors from rats fed the orange-pulp diet. Although the 15% orange-pulp diet did not change the number of tumors in the tumor-bearing rats, feeding rats orange pulp significantly decreased the number of endophytic tumors and increased the number of exophytic tumors. Increased activity of T cell killers in tumors and higher level of proteins involved with apoptosis following consumption of the orange pulp indicate a clear tumor suppressor effect of these dietary fibers.
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PMID:Effects of a 15% orange-pulp diet on tumorigenesis and immune response in rats with colon tumors. 1160 72

TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) is a member of the TNF family that promotes apoptosis by binding to the transmembrane receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. Its cytotoxic activity is relatively selective to the human tumor cell lines without much effect on the normal cells. Hence, it exerts an antitumor activity without causing toxicity, as apparent by studies with several xenograft models. This review discusses the intracellular mechanisms by which TRAIL induces apoptosis. The major pathway of its action proceeds through the formation of DISC and activation of caspase-8. The apoptotic processes, therefore, follow two signaling pathways, namely the mitochondrial-independent activation of caspase-3, and mitochondrial-dependent apoptosis due to cleavage of BID by caspase-8, the formation of apoptosomes, and activation of caspase-9 and the downstream caspases. Bcl-2 and Bcl-X(L) have no effect on TRAIL-induced apoptosis in lymphoid cells, whereas these genes block or delay apoptosis in nonlymphoid cancer cells. TRAIL participates in cytotoxicity mediated by activated NK cells, monocytes, and some cytotoxic T cells. Hence, TRAIL may prove to be an effective antitumor agent. In addition, it may enhance the effectiveness of treatment with chemotherapeutic drugs and irradiation. Nontagged Apo-2L/TRAIL does not cause hepatotoxicity in monkeys and chimpanzees and in normal human hepatocytes. Thus, nontagged Apo-2L/TRAIL appears to be a promising new candidate for use in the treatment of cancer.
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PMID:TRAIL/Apo-2L: mechanisms and clinical applications in cancer. 1177 36


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