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)

JP-8 induces apoptosis in rat lung epithelial cells, primary mouse T lymphocytes, Jurkat T lymphoma cells, and U937 monocytic cells (Stoica et al., 2001). Here, we have observed a different mechanism of cytotoxicity in human keratinocytes grown in culture as well as when grafted onto nude mice. At lower levels of JP-8 (80 microg/ml; 1 x 10(-4) dilution), sufficient to induce apoptosis in other cell types, including lung epithelial cells (Stoica et al., 2001), no apoptosis was observed. At higher levels (>200 microg/ml; 2.5 x 10(-4) dilution), JP-8 is cytotoxic to both primary and immortalized human keratinocytes, as evidenced by the metabolism of calcein, as well as by morphological changes such as cell rounding and cell detachment. There was no evidence of activation of caspases-3, -7, or -8 either by enzyme activity or immunoblot analysis, and the stable expression of a dominant-negative inhibitor of apoptosis (FADD-DN) did not increase the survival of keratinocytes to JP-8. The pattern of poly(ADP-ribose) polymerase (PARP) cleavage was also characteristic of necrosis. PARP has been also been implicated in necrosis via its ability to lower levels of ATP in damaged cells. However, fibroblasts derived from PARP-/- mice underwent necrotic cell death similar to those derived from PARP+/+ mice, indicating that the effects of JP-8 are independent of PARP. Immunoblot analysis further revealed that exposure of keratinocytes to the toxic higher levels of JP-8 markedly downregulates the expression of the prosurvival members of the Bcl-2 family, Bcl-2 and Bcl-x(L), and upregulates the expression of antisurvival members of this family, including Bad and Bak. Bcl-2 and Bcl-x(L) have been shown to preserve mitochondrial integrity and suppress cell death. In contrast, Bak and Bad both promote cell death by alteration of the mitochondrial membrane potential, in part by heterodimerization with and inactivation of Bcl-2 and Bcl-x(L), and either inducing necrosis or activating a downstream caspase program. High intrinsic levels of Bcl-2 and Bcl-x(L) may prevent apoptotic death of keratinocytes at lower levels of JP-8, while perturbation of the balance between pro- and antiapoptotic Bcl-2 family members at higher levels may ultimately play a role in necrotic cell death in human keratinocytes. Finally, when human keratinocytes were grafted to form a human epidermis on nude mice, treatment of these grafts with JP-8 revealed cytotoxicity and altered histology in vivo.
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PMID:Mechanisms of JP-8 jet fuel cell toxicity. II. Induction of necrosis in skin fibroblasts and keratinocytes and modulation of levels of Bcl-2 family members. 1122 86

The cytoplasmic adaptor protein FADD is an essential component of the death-inducing signaling complexes (DISCs) that assemble when TNF receptor family members, such as Fas, are ligated. FADD inititates the proteolytic cascade that leads to apoptosis by binding to and promoting the autocatalytic activation of caspase-8 [1-4]. Surprisingly, FADD (but not caspase-8) is also required for T cells to proliferate upon their stimulation with mitogens [5-9]. Using transgenic mice expressing a dominant-negative mutant of FADD (FADD-DN), we show that functional FADD is required for T cells to proliferate in response to antigens in vivo as well as to mitogens in culture. The costimulation of wild-type and FADD-DN T cells with mitogens revealed that FADD-DN T cells have a cell-autonomous defect in intracellular signaling. In contrast to another study [6], p53 deficiency did not rescue mitogen-induced proliferation of FADD-DN T cells, and neither did enforced expression of the apoptosis inhibitor Bcl-2. Like wild-type T cells, FADD-DN T cells stimulated with mitogens mobilized intracellular calcium and activated members of the NF-kappaB transcription factor family as well as p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK. Therefore, FADD must act downstream of or in parallel to these signaling pathways.
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PMID:Effects of a dominant interfering mutant of FADD on signal transduction in activated T cells. 1125 Jan 57

The Bcl-2 family of proteins plays a central regulatory role in apoptosis. We have identified a novel, widely expressed Bcl-2 member which we have named Bcl-rambo. Bcl-rambo shows overall structural homology to the anti-apoptotic Bcl-2 members containing conserved Bcl-2 homology (BH) motifs 1, 2, 3, and 4. Unlike Bcl-2, however, the C-terminal membrane anchor region is preceded by a unique 250 amino acid insertion containing two tandem repeats. No interaction of Bcl-rambo with either anti-apoptotic (Bcl-2, Bcl-x(L), Bcl-w, A1, MCL-1, E1B-19K, and BHRF1) or pro-apoptotic (Bax, Bak, Bik, Bid, Bim, and Bad) members of the Bcl-2 family was observed. In mammalian cells, Bcl-rambo was localized to mitochondria, and its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs, whereas inhibitors controlling upstream events of either the 'death receptor' (FLIP, FADD-DN) or the 'mitochondrial' pro-apoptotic pathway (Bcl-x(L)) had no effect. Surprisingly, the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain and not by the Bcl-2 homology region. Thus, Bcl-rambo constitutes a novel type of pro-apoptotic Bcl-2 member that triggers cell death independently of its BH motifs.
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PMID:Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension. 1126 95

Apoptosis in response to cellular stress such as treatment with cytotoxic drugs is mediated by effector caspases (caspase-3) which can be activated by different initiator pathways. Here, we report on a cell type specific triggering of death receptor and/or mitochondrial pathways upon drug treatment. In type I cells (BJAB), both the receptor and the mitochondrial pathway were activated upon drug treatment, since blockade of either the receptor pathway by overexpression of dominant negative FADD (FADD-DN) or of the mitochondrial pathway by overexpression of Bcl-X(L) only partially inhibited apoptosis. Drug treatment induced formation of a FADD- and caspase-8-containing CD95 death-inducing signaling complex (DISC) in type I cells resulting in activation of caspase-8 as the most apical caspase. In contrast, in type II cells (Jurkat), apoptosis was predominantly controlled by mitochondria, since overexpression of Bcl-2 completely blocked drug-induced apoptosis, while overexpression of FADD-DN had no protective effect. In these cells, caspases including caspase-8 were activated by mitochondria-driven signaling events and no DISC was detected despite expression levels of CD95, FADD and caspase-8 proteins comparable to type I cells. Likewise, drug-induced CD95 aggregation was predominantly found in type I cells. Bid was cleaved prior to mitochondrial alterations in type I cells providing a molecular link between caspase-8 activation and mitochondrial perturbations, whereas in type II cells, Bid was cleaved downstream of mitochondria. Our findings of a cell type specific response to cytotoxic drugs have implications for the identification of molecular parameters for chemosensitivity or resistance in different tumor cells.
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PMID:Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. 1131 43

Activation of the transcription factor nuclear factor-kappa B (NF-kappa B) has been found to play an essential role in the inhibition of tumor necrosis factor (TNF)-mediated apoptosis. NF-kappa B regulates several antiapoptotic molecules including inhibitors of apoptosis, Bcl-2 family proteins (A1 and Bcl-X(L))(,) and IEX-IL. Here we report that the expression of a small death effector domain (DED)-containing protein, NDED (NF-kappa B-inducible DED-containing protein), depends on the activation of NF-kappa B. The inhibition of NF-kappa B by I kappa B alpha, a natural inhibitor of NF-kappa B, suppressed NDED mRNA expression induced by TNF. The restoration of NDED in NF-kappa B null cells inhibited TNF-induced apoptosis. Intriguingly, unlike the caspase-8 inhibitor cellular FADD-like interleukin-1 beta converting enzyme-inhibitory protein (c-FLIP), NDED suppressed TNF-mediated apoptosis by inhibiting TNF-induced caspase-8 enzymatic activity but not the processing of caspase-8. Furthermore, NDED could not inhibit etoposide-mediated apoptosis that is independent of caspase-8 activation. Our results provide the first demonstration that NF-kappa B transcriptionally induces the DED-containing protein to suppress TNF-mediated apoptosis by inhibiting caspase-8 activity, which offers new insight into the antiapoptotic mechanism of NF-kappa B.
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PMID:Nuclear factor-kappa B-inducible death effector domain-containing protein suppresses tumor necrosis factor-mediated apoptosis by inhibiting caspase-8 activity. 1134 52

Tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines that promotes apoptosis. TRAIL induces apoptosis via death receptors (DR4 and DR5) in a wide variety of tumor cells but not in normal cells. The objectives of this study are to investigate the intracellular mechanisms by which TRAIL induces apoptosis. The death receptor Fas, upon ligand binding, trimerizes and recruits the adaptor protein FADD through the cytoplasmic death domain of Fas. FADD then binds and activates procaspase-8. It is unclear whether FADD is required for TRAIL-induced apoptosis. Here we show that the signaling complex of DR4/DR5 is assembled in response to TRAIL binding. FADD and caspase-8, but not caspase-10, are recruited to the receptor, and cells deficient in either FADD or caspase-8 blocked TRAIL-induced apoptosis. In addition, TRAIL initiates the activation of caspases, the loss of mitochondrial transmembrane potential (Deltapsi(m)), the cleavage of BID, and the redistribution of mitochondrial cytochrome c. Treatment of Jurkat cells with cyclosporin A delayed TRAIL-induced Deltapsi(m), caspase-3 activation and apoptosis. Similarly, Overexpression of Bcl-2 or Bcl-X(L) delayed, but did not inhibit, TRAIL-induced Deltapsi(m) and apoptosis. In contrast, XIAP, cowpox virus CrmA and baculovirus p35 inhibited TRAIL-induced apoptosis. These data suggest that death receptors (DR4 and DR5) and Fas receptors induced apoptosis through identical signaling pathway, and TRAIL-induced apoptosis via both mitochondrial-dependent and -independent pathways.
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PMID:Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. 1136 Jan 96

We have previously reported that mice with cardiac-specific overexpression of tumor necrosis factor (TNF)- alpha develop myocardial inflammation, cardiac hypertrophy, and dilated cardiomyopathy. TNF- alpha is reported to induce apoptosis in cultured cardiac myocytes. To investigate the role of apoptosis in this transgenic model, wild-type controls (WT) and transgenic mice (TG) at the age of 1, 8, and 40 weeks were analyzed. Increased incidence of apoptosis in TG was indicated by DNA laddering. TUNEL assays revealed that the frequencies of apoptotic cells were increased in the TG myocardium at all ages. However, as revealed by histochemical and immunofluorescent methods, most of the apoptotic cells appeared to be non-myocytes even in the mice with overt congestive heart failure. To elucidate the signaling pathways responsible for TNF- alpha induced apoptosis, expression of apoptosis-related genes were evaluated by multi-probe RNase protection assays. Transcripts for death-domain-related proteins, including TNFR1, Fas, FADD, TRADD, and RIP, were constitutively expressed in WT and upregulated in the TG myocardium. Expression of caspase-1 through -8 was also enhanced in TG. While both anti- and pro-apoptotic Bcl-2 family genes were constitutively expressed in WT, TNF- alpha overexpression strongly induced anti-apoptotic A1 in the myocardium. Furthermore, TNF- alpha overexpression activated NF- kappa B, a mediator of anti-apoptotic pathways, in the myocardium. Thus, overexpression of TNF- alpha activated both anti- and pro-apoptotic pathways in the myocardium, resulting in an increase of apoptosis, primarily in non-myocytes. These results suggest that TNF- alpha by itself is not sufficient to induce apoptosis in cardiac myocytes in vivo.
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PMID:Overexpression of tumor necrosis factor- alpha activates both anti- and pro-apoptotic pathways in the myocardium. 1143 39

FasL and TNF-related apoptosis-inducing ligand (TRAIL) belong to a subgroup of the TNF superfamily which induce apoptosis by binding to their death domain containing receptors. In the present study we have utilized a panel of seven cell lines derived from human malignant gliomas to characterize molecular pathways through which FasL and TRAIL induce apoptosis in sensitive glioma cells and the mechanisms of resistance in cell lines which survive the death stimuli. Our findings indicate that FADD and Caspase-8 are essential for FasL and TRAIL mediated apoptosis in glioma cells. One sensitive cell line (D270) can be protected from FasL and TRAIL induced death by anti-apoptotic Bcl-2 family members while another (D645) cannot, implying that these lines may represent glioma examples of type II and type I cells respectively. For the first time we demonstrate resistance to FasL but not to TRAIL within the one glioma cell line. Furthermore, we report distinct mechanisms of resistance within different glioma lines, including downregulation of Caspase-8 in U373MG. Cycloheximide sensitized four of the resistant cell lines suggesting the presence of labile inhibitors. None of the known apoptosis inhibitors examined accounted for the observed resistance, suggesting novel inhibitors may exist in glioma cells.
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PMID:Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells. 1159 84

Ultraviolet (UV) light is a potent mutagenic and genotoxic agent. Whereas DNA damage induced by UV light is known to be responsible for UV-induced genotoxicity, its role in triggering apoptosis is still unclear. We addressed this issue by comparing nucleotide excision repair (NER) deficient 27-1 and 43-3B Chinese hamster (CHO) cells with the corresponding wild-type and ERCC-1 complemented cells. It is shown that NER deficient cells are dramatically hypersensitive to UV-C induced apoptosis, indicating that DNA damage is the major stimulus for the apoptotic response. Apoptosis triggered by UV-C induced DNA damage is related to caspase- and proteosome-dependent degradation of Bcl-2 protein. The expression of other members of the Bcl-2 family such as Bax, Bcl-x(L) and Bak were not affected. Bcl-2 decline is causally involved in UV-C induced apoptosis since overexpression of Bcl-2 protected NER deficient cells against apoptosis. We also demonstrate that caspase-8, caspase-9 and caspase-3 are activated and PARP is cleaved in response to unrepaired UV-C induced DNA damage. Caspase-8 activation occurred independently of CD95 receptor activation since CD95R/FasR and CD95L/FasL were not altered in expression, and transfection of transdominant negative FADD failed to block apoptosis. Overall, the data demonstrate that UV-C induced non-repaired DNA damage triggers apoptosis in NER deficient fibroblasts involving components of the intrinsic mitochondrial damage pathway.
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PMID:Ultraviolet light-induced DNA damage triggers apoptosis in nucleotide excision repair-deficient cells via Bcl-2 decline and caspase-3/-8 activation. 1159 10

The tumor necrosis factor (TNF) receptor family are ligand-regulated transmembrane proteins that mediate apoptosis as well as activation of the transcription factor NF-kappaB. Exogenous expression of DR6, a recently identified member of the TNF receptor family, induced apoptosis in untransformed or tumor-derived cells and the apoptotic function of DR6 was inhibited by co-expression of Bcl-2, Bcl-x(L) or the inhibitor-of-apoptosis (IAP) family member, survivin. Expression of a dominant negative mutant of FADD failed to protect from DR6-mediated apoptosis indicating that unlike TNFR1 and Fas, DR6 induced apoptosis via a FADD-independent mechanism. Despite the ability of exogenous DR6 expression to induce apoptosis, DR6 mRNA and protein were found to be elevated in prostate tumor cell lines and in advanced stages of prostate cancer. Analysis of several anti-apoptotic proteins revealed that Bcl-x(L) levels and serine 32 phosphorylation of IkappaB, the natural inhibitor of NF-kappaB, were similarly elevated in cells expressing high levels of DR6, suggesting that NF-kappaB-regulated survival proteins may protect from DR6-induced apoptosis and that DR6 is a target of NF-kappaB regulation. Treatment of LnCAP cells with TNF-alpha resulted in increases in both DR6 mRNA and protein levels, and this induction was suppressed by inhibitors of NF-kappaB. Similarly, treatment of cells expressing high levels of DR6 with indomethacin and ibuprofen, compounds also known to perturb NF-kappaB function, resulted in a dose-dependent decrease in DR6 protein and mRNA levels. These results demonstrate that TNF-alpha signaling induces the expression of a member of its own receptor family through activation of NF-kappaB.
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PMID:Tumor necrosis factor-alpha induces the expression of DR6, a member of the TNF receptor family, through activation of NF-kappaB. 1175 79


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