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)

The hallmarks of rheumatoid arthritis (RA) are leukocytic infiltration of the synovium and expansiveness of fibroblast-like synoviocytes (FLS). The abnormal proliferation of FLS and their resistance to apoptosis is mediated, at least in part, by present in RA joints proinflammatory cytokines and growth factors. Because IL-15 exerts properties of antiapoptotic and growth factors, and is produced by RA FLS, we hypothesized that IL-15 participates in RA FLS activation. To test this hypothesis, we first examined whether RA FLS express chains required for high affinity functional IL-15R. Indeed, RA FLS express IL-15Ralpha at mRNA and protein levels. Moreover, we confirmed the presence of IL-2Rbeta and common gamma-chains. Interestingly, TNF-alpha or IL-1beta triggered significant elevation of IL-15Ralpha chain at mRNA and protein levels. Next, we investigated the effects of exogenous or endogenous IL-15 on Bcl-2 and Bcl-x(L) expression, FLS proliferation, and apoptosis. Exogenous IL-15 enhanced RA FLS proliferation and increased the level of mRNA-encoding Bcl-x(L). To test the role of endogenous IL-15 in the activation of RA FLS, an IL-15 mutant/Fcgamma2a protein exerting properties of specific antagonist to the IL-15Ralpha chain was used. We found that blocking IL-15 biological activities using this protein substantially reduced endogenous expression of Bcl-2 and Bcl-x(L), and RA FLS proliferation that was reflected by increased apoptosis. Thus, we have demonstrated that a distinctive phenotype of RA FLS, i.e., persistent activation, proliferation, and resistance to apoptosis, is related to the autocrine activation of IL-15Rs by FLS-derived IL-15.
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PMID:Fibroblast-like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression of Bcl-x(L) and Bcl-2. 1216 97

Tumor necrosis factor (TNF)-alpha and TNF-related apoptosis inducing ligand (TRAIL) share a common signaling pathway. Here we show a novel potentiating effect of cadmium on TNF-alpha- or TRAIL-mediated cell death via distinct signaling. TNF-alpha or TRAIL sensitized otherwise resistant NIH3T3 embryo fibroblast cells to death, when exposed to cadmium. The potentiating effects elicited by TNF-alpha or TRAIL on cell death were NF-kappaB- and SAPK/JNK-independent and were not diminished by the expression of Bcl-2. TNF-alpha potentiated the cadmium-induced accumulation of p53 but did not affect expression levels of Bax, Mdm2 and p21(WAF/CIP). A similar pattern of p53 accumulation was also observed in Balbc/3T3 fibroblasts but not in human tumor cell lines, MCF7 and HeLa cells. The synergistic cell death evoked by TNF-alpha and cadmium was attenuated by transient expression of a dominant negative p53(Val135) mutant in NIH3T3 cells and was not observed in p53(-/-) mouse embryo fibroblasts, indicating that p53 accumulation appears to contribute to cell death. In contrast, TRAIL did not further increase the cadmium-induced accumulation of p53 despite its potentiation effects on the cadmium-induced cell death. Expression of p53(Val135) mutant did not reduce TRAIL- and cadmium-mediated cell death. Taken together, these results suggest that TNF-alpha and TRAIL potentiate the cadmium-mediated cell death via distinct p53 expression patterns.
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PMID:Sensitizing effects of cadmium on TNF-alpha- and TRAIL-mediated apoptosis of NIH3T3 cells with distinct expression patterns of p53. 1218 81

Cross-linking of the B cell antigen receptor (BCR) on germinal center B cells can induce growth arrest and apoptosis, thereby eliminating potentially autoreactive B cells. Using the Burkitt lymphoma cell line Ramos as a model, we studied the commitment to apoptosis following growth arrest, as well as how triggering of CD40 or addition of tumor necrosis factor (TNF)-alpha can interfere to block cell death. Both BCR triggering and direct induction of growth arrest by sodium butyrate (n-But) caused hypophosphorylation of the retinoblastoma protein (pRb), followed by apoptosis. Interestingly, although CD40 ligation or TNF-alpha efficiently prevented BCR-induced and n-But-induced apoptosis, these co-stimuli did not inhibit, but rather augmented, growth arrest. Analysis of cell cycle regulators showed that each apoptotic and T(h) stimulus distinctly affected cyclins or cyclin-dependent kinase inhibitors, indicating that growth arrest can be uncoupled from apoptosis. BCR ligation and growth arrest activated the intrinsic or mitochondrial route of apoptosis. CD40 ligation and TNF-alpha prevented release of cytochrome c and activation of caspase-3, which could not be explained by effects on the expression of Bcl-2, Bcl-x(L) or Bax. Finally, the onset of BCR-induced apoptosis occurred after 10-12 h and addition of CD40 mAb or TNF-alpha at that point still prevented further execution of apoptosis. We conclude that in mature B cells apoptosis is not an obligatory event following growth arrest. Instead, commitment to apoptosis can be rapidly controlled by T cells via CD40 ligand and TNF-alpha, downstream of the pRb-regulated restriction point of the cell cycle, but prior to mitochondrial cytochrome c release.
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PMID:Prevention of B cell antigen receptor-induced apoptosis by ligation of CD40 occurs downstream of cell cycle regulation. 1220 95

We studied the expression of Bcl-2 family proteins during cytokine- and verotoxin (VT)-induced apoptosis in primary human umbilical vein endothelial cells (HUVECs). Our experiments demonstrated that high initial expression of Bcl-2 protein was significantly downregulated in HUVECs treated with IFN-gamma whereas TNF-alpha gave a less pronounced decrease in Bcl-2 level. Treatment with the combination of cytokines was more efficient in downregulating Bcl-2 protein. HUVECs pretreated with cytokines and incubated with VT gave a further significant decrease in Bcl-2 level. Simultaneous measurement of Bcl-xl level did not reveal any significant changes. Bax protein was upregulated in HUVECs stimulated with TNF-alpha alone or in combination with IFN-gamma. However, addition of VT did not give any further increase in Bax level suggesting that Bax upregulation is more important for cytokine- rather than VT-mediated apoptosis. Total endothelial cell growth factor deprivation gave a significant increase in apoptosis accompanied by a decrease of Bcl-2 in apoptotic cells while Bcl-xl and Bax levels were unaffected. Our data indicate that anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax are reciprocally regulated during apoptosis, whilst Bcl-xl is essentially unaffected. This implies that Bcl-2/Bax ratio rather than Bcl-xl controls apoptosis in primary endothelial cells.
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PMID:Modulation of Bcl-2 family proteins in primary endothelial cells during apoptosis. 1221 54

Most cells are naturally resistant to TNF-alpha-induced cell death and become sensitized when NF-kappaB transactivation is blocked or in the presence of protein synthesis inhibitors that prevent the expression of anti-apoptotic genes. In this report we analyzed the role of osmotic stress on TNF-alpha-induced cell death. We found that it sensitizes the naturally resistant HeLa cells to TNF-alpha-induced apoptosis, with the involvement of an increase in the activity of several kinases, the inhibition of Bcl-2 expression, and a late increase on NF-kappaB activation. Cell death occurs regardless of the enhanced NF-kappaB activity, whose inhibition produces an increase in apoptosis. The inhibition of p38 kinase, also involved in NF-kappaB activation, significantly increases the effect of osmotic stress on TNF-alpha-induced cell death.
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PMID:Osmotic stress sensitizes naturally resistant cells to TNF-alpha-induced apoptosis. 1223 97

The human corpus luteum (CL) is a transient endocrine organ with a life span of 14-16 days. Apoptosis has been suggested to be the mechanism of CL regression and the possible regulatory role of the bcl-2 family in this process has been studied in animals and, to some extent, in humans. In the present study, apoptosis was studied in the human CL and in luteinised granulosa cells by in situ 3'-end labelling and gel electrophoretic DNA fragmentation analysis. The apoptosis-regulating factors Bcl-2, Bax and TNF-alpha, transcription factor NF-kappaB and Caspase-3, a key executioner protein in apoptotic cell death, were studied by immunohistochemistry and in situ hybridisation. Furthermore, we analysed expression of 17beta hydroxysteroid dehydrogenase (17HSD) type 1 and 2, key enzymes in the estrogen metabolism. Apoptosis was found in the CL throughout the luteal phase, but a marked increase of apoptotic luteal cells was observed during the late luteal phase (CL day 11-14). This was preceded by a clear increase of 17HSD type 1 expression. The apoptosis-regulating proteins Bcl-2 and Bax were expressed constantly in the CL throughout the luteal phase. TNF-alpha expression was constant during the early and mid-luteal phases, but in the late luteal phase, some specimens showed increased immunostaining. NF-kappaB and Caspase-3 were present in the CL throughout the luteal phase and in individual specimens, the expression of Caspase-3 was associated with a high rate of apoptosis in the late luteal phase. In conclusion, apoptosis is involved in human luteal regression and estradiol (E(2)) may function as a trigger for this process. The expression of the pro- and anti-apoptotic factors studied in the CL suggest their part in this process, but the conclusive evidence for the exact molecular mechanisms remains open.
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PMID:Role of apoptosis, apoptosis-related factors and 17beta-hydroxysteroid dehydrogenases in human corpus luteum regression. 1224 42

TNF-alpha elicits various responses including apoptosis, proliferation, and differentiation according to cell type. In neuronal PC12 cells, TNF-alpha induces moderate apoptosis while lipopolysarccaharide or trophic factor deprivation can potentiate apoptosis that is induced by TNF-alpha. TNF-alpha initiates various signal transduction pathways leading to the activation of the caspase family, NF-subk;B, Jun N-terminal kinase, and p38 MAPK via the death domain that contains the TNF-alpha receptor. Inhibition of translation using cycloheximide greatly enhanced the apoptotic effect of TNF-alpha. This implies that the induction of anti-apoptotic genes for survival by TNF-alpha may be able to protect PC12 cells from apoptosis. Accordingly, Bcl-2, an anti-apoptotic Bcl-2 family member, was highly expressed in response to TNF-alpha. In this study, we examined the anti-apoptotic role of p38 MAPK that is activated by TNF-alpha in neuronal PC12 cells. The phosphorylation of p38 MAPK in response to TNF-alpha slowly increased and lasted several hours in the PC12 cell and DRG neuron. This prolonged and slow phosphorylation of p38 MAPK was distinct from other non-neuronal cells. The specific inhibitor of p38 MAPK, SB202190, significantly enhanced the apoptosis that was induced by TNF-alpha in PC12 cells. This indicates that the activation of p38 MAPK could protect PC12 cells from apoptosis since there is no known role of p38 MAPK in response to TNF-alpha in neuron. This discovery could be evidence for the neuroprotective role of the p38 MAPK.
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PMID:Role of p38 MAPK in the regulation of apoptosis signaling induced by TNF-alpha in differentiated PC12 cells. 1229 9

By using our recently developed gene discovery system, we have identified Bak, a member of the Bcl-2 family, as a pro-apoptotic factor in the tumor necrosis factor (TNF)-alpha-induced apoptotic pathway in caspase 3-deficient cells. Unlike Bcl-2, Bak stimulates several apoptotic pathways, however the molecular mechanism(s) of its action remains unclear. For example, it is unclear whether Bak induces apoptosis in caspase 3-deficient cells. In this study, we examined the effects of overexpression of Bak in MCF-7 cells that lack caspase 3. We found that despite the absence of caspase 3 in MCF-7 cells, they were more sensitive to the cell death effects of Bak as compared to caspase 3-expressing HeLa S3 cells. The targeting of Bak function by ribozymes suggests that Bak is required for the TNF-alpha-induced apoptotic pathway in caspase 3-deficient cells. This study demonstrates the caspase 3-independent function of Bak in the TNF-alpha-induced apoptotic pathway.
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PMID:Identification of a caspase 3-independent role of pro-apoptotic factor Bak in TNF-alpha-induced apoptosis. 1229 81

Calorie restriction (CR) is known to delay the aging process in rodents and is postulated to act by decreasing free radical generation and increasing antioxidant enzyme activity. The present study was designed to investigate the effect of CR and age on oxidative stress-induced apoptosis and associated changes in the levels of TNF-alpha, and Bcl-2 in splenic T lymphocytes. Ad libitum (AL)- or CR-fed C57BL/6J mice were sacrificed either at 6 (young) or 18 (old) months and splenic lymphocytes were incubated with or without 25 micro M H2O2 to induce apoptosis. Apoptosis increased with age in cells of AL-fed mice incubated with H2O2. CR prevented this rise in apoptosis in total splenic lymphocytes and in CD4(+) and CD8(+) T lymphocyte subsets either with or without H2O2. Free radicals increased and mitochondrial membrane potential decreased in aged mice. CR prevented these changes and also prevented the age-associated increase in TNF-alpha and loss of Bcl-2 in total splenic lymphocytes and in CD4(+) and CD8(+) lymphocyte subsets. In summary, lymphocytes in aged AL-fed mice were much more susceptible to oxidative stress-induced apoptosis whereas CR normalized apoptosis by preventing the increase in TNF-alpha and the decrease in Bcl-2 associated with aging.
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PMID:Inhibition of H2O2-induced apoptosis of lymphocytes by calorie restriction during aging. 1242 90

The effects of the PKC activator and down-regulator bryostatin 1 and the PKC and Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) were compared with respect to potentiation of 1-beta-D-arabinofuranosylcytosine (ara-C)-induced apoptosis in human myelomonocytic leukemia cells (U937). Whereas bryostatin 1 and UCN-01 both markedly enhanced ara-C-induced mitochondrial injury (e.g., cytochrome c and Smac/DIABLO release, loss of mitochondrial membrane potential), caspase activation, and apoptosis, ectopic expression of an N-terminal loop-deleted Bcl-2 mutant protein protected cells from ara-C/UCN-01- but not ara-C/bryostatin 1-mediated lethality. Conversely, ectopic expression of CrmA or dominant-negative caspase-8 abrogated potentiation of ara-C-mediated apoptosis by bryostatin 1 but not by UCN-01. Exposure of cells to ara-C and bryostatin 1 (but not UCN-01) resulted in sustained release of tumor necrosis factor (TNF) alpha; moreover, potentiation of ara-C lethality by bryostatin 1 (but not by UCN-01) was reversed by coadministration of TNF soluble receptors or the selective PKC inhibitor bisindolylmaleimide (1 microM). Finally, similar events were observed in the human promyelocytic leukemia cell line HL-60. Together, these findings suggest that potentiation of ara-C lethality in human myeloid leukemia cells by bryostatin 1 but not UCN-01 involves activation of the extrinsic, receptor-mediated apoptotic pathway, and represents a consequence of bryostatin 1-mediated release of TNF-alpha. They also argue that the mechanism by which bryostatin 1 promotes ara-C-induced mitochondrial injury, caspase activation, and apoptosis involves factors other than or in addition to PKC down-regulation or modulation of Bcl-2 phosphorylation status.
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PMID:Bryostatin 1 and UCN-01 potentiate 1-beta-D-arabinofuranosylcytosine-induced apoptosis in human myeloid leukemia cells through disparate mechanisms. 1248 56


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