Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preclinical studies in animal models and human clinical trials have evaluated the safety and efficacy of adenoviral vectors for cancer gene therapy. These studies have indicated that gene delivery via adenoviral vectors, including p53 gene therapy, represents a promising therapeutic modality for many types of human cancers. This review focuses on novel strategies to induce apoptosis in glioma cells by transduction with adenoviral vectors carrying a variety of apoptosis-related genes, including Fas ligand, Fas, FADD, caspase-8, p53, p33ING1, p73alpha, Bax, Apaf-1, caspase-9, IkappaBdN, caspase-3, Bcl-2, and Bcl-X(L). We conclude that adenoviral vector-mediated delivery of apoptosis-related genes other than p53 is a potentially useful gene therapy approach toward the treatment of human brain tumors.
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PMID:Gene therapy using an adenovirus vector for apoptosis-related genes is a highly effective therapeutic modality for killing glioma cells. 1265 7

The p53 mutant 143Ala is a human temperature-sensitive mutant with two conformational states. To definitively determine whether the Fas signal transduction pathway and the function of the pathway are dependent on p53 status, we have established stable transfectants of p53 mutant 143Ala in two human cancer cell lines: H1299 (lung cancer line) and PC-3 (prostate cancer line), the native state of which contains null p53 status and can grow at 37 degrees C and 32.5 degrees C. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell cycle analysis showed inhibition of the growth of cells overexpressing p53 mutant 143Ala in the wild-type p53 form at 32.5 degrees C because of induction of G0/G1 arrest. Transfected cells had increased protein expression of p21, Fas, and MDM2 at the wild-type p53 conformation at 32.5 degrees C, but not in the mutant p53 form at 37 degrees C. However, there was no change in protein expression of FADD, FAP-1, Bcl-2, or Bax at 32.5 or 37 degrees C. Assays for apoptosis demonstrated that anti-Fas antibody CH-11 and FasL induced apoptosis only in cells that overexpress p53 mutant 143Ala at 32.5 degrees C with the wild-type p53 form. Both caspase-3 and caspase-8 activities were increased by anti-Fas antibody CH-11 only in cells at 32.5 degrees C with wild-type p53. Our results demonstrated that Fas-mediated apoptosis in H1299 and PC-3 cells expressing p53 mutant 143Ala occurred only with the wild-type p53 phenotype. These results support the hypothesis that Fas-mediated apoptosis is dependent, at least partially, on the presence of a functional wild-type p53 state. This model may be a useful tool for dissecting the specific interactions between wild-type p53 and the Fas signal transduction pathway in human cancer cells.
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PMID:Fas-mediated apoptosis is dependent on wild-type p53 status in human cancer cells expressing a temperature-sensitive p53 mutant alanine-143. 1267 Sep

Tumor necrosis factor related apoptosis inducing ligand (TRAIL) belongs to the Tumor necrosis factor (TNF) family of death-inducing ligands, and signaling downstream of TRAIL ligation to its receptor(s) remains to be fully elucidated. Components of the death-inducing signaling complex (DISC) and TRAIL signaling downstream of receptor activation were examined in TRAIL - sensitive and -resistant models of human rhabdomyosarcoma (RMS). TRAIL ligation induced DISC formation in TRAIL-sensitive (RD, Rh18, Rh30) and TRAIL-resistant RMS (Rh28, Rh36, Rh41), with recruitment of FADD and procaspase-8. In RD cells, overexpression of dominant-negative FADD (DNFADD) completely abolished TRAIL-induced cell death in contrast to dominant-negative caspase- 8 (DNC8), which only partially inhibited TRAIL-induced apoptosis, growth inhibition, or loss in clonogenic survival. DNC8 did not inhibit the cleavage of Bid or the activation of Bax. Overexpression of Bcl-2 or Bcl-xL inhibited TRAIL-induced apoptosis, growth inhibition, and loss in clonogenic survival. Bcl-2 and Bcl-xL, but not DNC8, inhibited TRAIL-induced Bax activation. Bcl-xL did not inhibit the early activation of caspase-8 (<4 h) but inhibited cleavage of Bid, suggesting that Bid is cleaved downstream of the mitochondria, independent of caspase-8. Exogenous addition of sphingosine also induced activation of Bax via a caspase-8-and Bid-independent mechanism. Further, inhibition of sphingosine kinase completely protected cells from TRAIL-induced apoptosis. Data demonstrate that in RMS cells, the TRAIL signaling pathway circumvents caspase-8 activation of Bid upstream of the mitochondria and that TRAIL acts at the level of the mitochondria via a mechanism that may involve components of the sphingomyelin cycle.
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PMID:A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells. 1276 81

Many apoptotic pathways culminate in the activation of caspase cascades usually triggered by the apical caspases-8 or -9. We describe a paradigm where apoptosis is initiated by the effector caspase-3. Diethylmaleate (DEM)-induced apoptotic damage in Jurkat cells was blocked by the anti-apoptotic protein Bcl-2, whereas, a peptide inhibitor of caspase-3 but not caspase-9 blocked DEM-induced mitochondrial damage. Isogenic Jurkat cell lines deficient for caspase-8 or the adaptor FADD (Fas associated death domain) were not protected from DEM-induced apoptosis. Caspase-3 activation preceded that of caspase-9 and initial processing of caspase-3 was regulated independent of caspase-9 and Bcl-2. However, inhibitors of caspase-9 or caspase-6 regulated caspase-3 later in the pathway. We explored the mechanism by which caspase-3 processing is regulated in this system. DEM triggered a loss of Erk-1/2 phosphorylation and XIAP (X-linked inhibitor of apoptosis protein) expression. The phorbol ester PMA activated a MEK-dependent pathway to block caspase-3 processing and cell death. Constitutively active MEK-1 (CA-MEK) upregulated XIAP expression and exogenous XIAP inhibited DEM-induced apoptotic damage. Thus, we describe a pathway where caspase-3 functions to initiate apoptotic damage and caspase-9 and caspase-6 amplify the apoptotic cascade. Further, we show that MEK may regulate caspase-3 activation via the regulation of XIAP expression in these cells.
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PMID:Caspase-3 activation is an early event and initiates apoptotic damage in a human leukemia cell line. 1281 79

Activation-induced cell death and cytokine deprivation are demonstrated by peripheral T cell populations at the conclusion of natural immune responses, and each of these processes is modulated by the immunosuppressive cytokine interleukin (IL)-10 in vitro. This study employs a clinically relevant in vivo model of IL-10 gene transfer with heterotopically transplanted cardiac allografts to determine the mechanisms of the effects of IL-10 on T cell survival. IL-10 protein overexpression within allografts 4-5 days after gene transfer augments apoptosis of CD4+ and CD8+ graft-infiltrating lymphocytes by 7.1-fold (P < 0.001) and 6.0-fold (P < 0.001), respectively. Graft-infiltrating T cells express 10-fold more proapoptotic Fas (P < 0.01) and 30-fold more Bax (P < 0.01) than controls. The fractions of activated caspase-8 (FADD-like IL-1beta-converting enzyme) and activated caspase-9 were increased 7- and 2.3-fold, respectively, in IL-10 gene-treated allografts at postoperative day 4-5. These changes in the Fas-Fas ligand pathway and Bcl-2 mitochondrial apoptosis regulation are enhanced by complete suppression of antiapoptotic FADD-like IL-1beta-converting enzyme inhibitory protein (FLIP) (from 30.5 to 0.0%, P < 0.01) and Bcl-xL (from 22.5 to 0.1%, P = 0.03) expression among these cells from the earliest days after gene transfer. Although changes in proteins of Fas- and Bcl-2-mediated apoptosis signaling occur, only the levels of Fas and FLIP correlate to the rate of apoptosis of graft-infiltrating CD3 lymphocytes and histological rejection scores. These results indicate that dichotomous apoptosis-regulatory pathways are affected by IL-10 gene therapy, but Fas-mediated mechanisms of activation-induced cell death more substantially contribute to the greater cell death of graft-infiltrating T cells after ex vivo IL-10 gene transfer.
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PMID:Dual upregulation of Fas and Bax promotes alloreactive T cell apoptosis in IL-10 gene targeting of cardiac allografts. 1291 85

Calicheamicin thetaII is a member of the enediyne class of antitumor antibiotics that bind to DNA and induce apoptosis. These compounds differ, however, from conventional anticancer drugs as they bind in a sequence-specific manner noncovalently to DNA and cause sequence-selective oxidation of deoxyriboses and bending of the DNA helix. Calicheamicin is clinically employed as immunoconjugate to antibodies directed against, for example, CD33 in the case of gemtuzumab ozogamicin. Here, we show by the use of the unconjugated drug that calicheamicin-induced apoptosis is independent from death-receptor/FADD-mediated signals. Moreover, calicheamicin triggers apoptosis in a p53-independent manner as shown by the use of p53 knockout cells. Cell death proceeds via activation of mitochondrial permeability transition, cytochrome c release and activation of caspase-9 and -3. The overexpression of Bcl-x(L) or Bcl-2 strongly inhibited calicheamicin-induced apoptosis. Knockout of Bax abrogated cell death after calicheamicin treatment. Thus, the activation of mitochondria and execution of cell death occur through a fully Bax-dependent mechanism. Interestingly, caspase inhibition by the pancaspase-inhibitor zVAD-fmk interfered with mitochondrial activation by calicheamicin. This places caspase activation upstream of the mitochondria and indicates that calicheamicin-triggered apoptosis is enhanced through death receptor-independent activation of the caspase cascade, that is, an amplification loop that is required for full activation of the mitochondrial pathway.
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PMID:Induction of apoptosis by enediyne antibiotic calicheamicin thetaII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner. 1464 46

Abnormal Tau protein is known to be closely associated with several neurodegenerative diseases. Previously, we showed that Tau was cleaved by caspase-3 to generate the cleavage product lacking the C-terminus (DeltaTau-1) during neuronal cell death. Here we characterized caspase-8-dependent neurotoxicity of the truncated Tau. Introduction of DeltaTau-1 into primary hippocampal neurons induced loss of neurites in a caspase-dependent manner. Caspase-8 and -6 were proteolytically activated during DeltaTau-1-triggered neuronal cell death, which was suppressed by IETD-fmk, caspase-8 inhibitor. Direct targeting of caspase-8 and its associated FADD with antisense approaches and transient expression of their dominant-negative mutants reduced DeltaTau-1-induced apopotosis. Cells deficient in caspase-8, but not caspase-3, became sensitized to DeltaTau-1-mediated toxicity upon reconstitution with caspase-8. In addition, ectopic expression of mitochondrial antiapoptotic Bcl-2, Bcl-X(L), or inactive caspase-9 short form suppressed DeltaTau-1 toxicity. These results suggest that the truncated Tau protein activates proximal caspase-8 through FADD as a necessary step leading to neuronal cell death and neurite regression, contributing to the progression of abnormal Tau-associated neurodegeneracy.
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PMID:Atypical role of proximal caspase-8 in truncated Tau-induced neurite regression and neuronal cell death. 1467 71

We have demonstrated previously a Fas-dependent component in thymineless death of human colon carcinoma cells. Importantly, the cytotoxic effects of thymidine deprivation induced by 5-fluorouracil (FUra) combined with leucovorin (LV) was enhanced by IFN-gamma, and the synergism was shown to be dependent on Fas, FUra-induced DNA damage, and independent of p53. Subsequently we examined the potential for synergistic interactions between IFN-gamma and the specific thymidylate synthase inhibitor, ZD9331. IFN-gamma sensitized colon carcinomas to ZD9331-induced apoptosis and loss in clonogenic survival, also dependent on ZD9331-induced DNA damage, independent of p53. Synergism occurred in HCT116, demonstrating previously RNA-mediated FUra/LV cytotoxicity that could not be potentiated by IFN-gamma. Manipulation of the Fas death receptor pathway from the level of the receptor (Nok1/Nok2, Fas overexpression, and DN-FADD) to the mitochondria (Bcl-xL and Bcl-2) did not modulate ZD9331 +/- IFN-gamma-induced cytotoxicity in HT29, with the exception that Nok1/Nok2-blocking antibodies partially protected HT29 from the cytotoxic activity of ZD9331 alone. However, IFN-gamma alone (but not ZD9331) up-regulated the expression of caspases -3, -4, -7, and -8, and in combination with ZD9331 demonstrated enhanced caspase activation and cleavage of poly(ADP-ribose) polymerase that was not prevented by overexpression of Bcl-2. Additionally, IFN-gamma increased the activity of the proteasome in HT29, leading to selective down-regulation of the antiapoptotic protein survivin, whereas simultaneously increasing Fas expression. However, reduction in the survivin:Fas ratio by transfection of survivin small interfering RNA and/or overexpression of Fas did not affect sensitivity of HT29 to ZD9331 +/- IFN-gamma. Data demonstrate that IFN-gamma combined with ZD9331 is synergistic in additional cell lines that demonstrate RNA-mediated FUra/LV cytotoxicity, and that a major target of interaction is at the level of caspases, downstream of Fas, and independent of involvement of either the mitochondria or survivin.
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PMID:Interferon-gamma-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the inhibitor of apoptosis survivin. 1469 55

Multiple mechanisms exist by which tumour cells can escape CD95-mediated apoptosis. Previous studies by our laboratory have shown that primary B cells from non-Hodgkin's Lymphoma (B-NHL) were resistant to CD95-induced cell death. In the current study, we have analysed the mechanisms underlying CD95 resistance in primary human lymphoma B cells. We report that FADD (FAS-associated death domain protein) and caspase-8 were constitutively expressed in lymphoma B cells and that the CD95 pathway was blocked upstream to caspase-8 activation. However, caspase-8 was processed and functional after treatment with staurosporine (STS). We found that the expression levels of FLICE (FADD-like interleukin-1 beta-converting enzyme)-Inhibitory Protein (c-FLIP) and Bcl-2-related proteins were heterogeneous in B-NHL cells and were not related to CD95 resistance. Finally, we report the absence of a CD95-induced signalling complex [death-inducing signalling complex (DISC)] in lymphoma B cells, with no FADD and caspase-8 recruitment to CD95 receptor. In contrast, DISC formation was observed in CD95-resistant non-tumoural (NT) B cells. Therefore, we propose that the absence of DISC formation in primary lymphoma B cells may contribute to protect these cells from CD95-induced apoptosis.
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PMID:Impairment of death-inducing signalling complex formation in CD95-resistant human primary lymphoma B cells. 1500 62

Cellular senescence and apoptosis are two metabolically related and seemingly synergistic processes that are involved in tissue maintenance and homeostasis, anti-tumor protection, and age-related diseases. Despite this apparent co-operativity, senescence can inhibit apoptosis in certain conditions. Here, we describe senescence-apoptosis relationships in human epidermal cells by comparing apoptosis-related effector concentrations in keratinocyte cultures and epidermal skin cells at various stages of ageing. Using western blots, flow cytometry, enzyme-linked immuno-sorbent assay (ELISA) and immunofluorescence, we determined the amounts of apoptotic effectors in aged cells compared to young ones, in parallel with beta-galactosidase activity at neutral pH (senescence-associated beta-galactosidase, SA beta-gal), found to be a good indicator of cellular ageing. We observed increased levels of several Fas-mediated apoptosis effectors (Fas, Fas ligand, FADD, FLICE), both in cell cultures at advanced passages and in skin cells of aged donors (above 45 years). Furthermore, we found that while the pro-apoptotic p53 increased, the anti-apoptotic Bcl-2 declined. In spite of this, the extent of spontaneous apoptosis did not change in senescent keratinocyte cultures. The cells, however, became notably more susceptible to apoptosis when kept in exhausted growth medium, or upon Fas receptor activation by anti-Fas antibody binding. Our results are consistent with recent findings in senescent fibroblasts, showing that the death-signaling pathway is enhanced at senescence.
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PMID:Enhancement of Fas-mediated apoptosis in ageing human keratinocytes. 1501 68


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