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 sIgG(+) lymphoblastoid B cell line CESS spontaneously produces a high amount of NGF and expresses both high affinity (p140(Trk-A)) and low affinity (p75(NTR)) NGF receptors. Blocking NGF signals with neutralizing antibodies or specific Trk-A inhibitors induces a rapid phosphorylation of antiapoptotic Bcl-2 protein, followed by caspase activation, and apoptotic death of CESS cells. Bcl-2 phosphorylation in several sites within a approximately 60 aa "loop" domain of protein is known to regulate its antiapoptotic function. Accordingly, CESS cells expressing the loop deletional mutant cDNA constructs Bcl-2 Delta40-91 were completely resistant to apoptosis induced by NGF withdrawal, indicating that Bcl-2 phosphorylation is a critical event. NGF withdrawal induces p38 MAPK, but not JNK, activation in CESS cells, and SB203580, a specific inhibitor of p38 MAPK, is able to prevent both Bcl-2 phosphorylation and apoptosis, indicating that p38 MAPK is the enzyme responsible for these events.
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PMID:NGF withdrawal induces apoptosis in CESS B cell line through p38 MAPK activation and Bcl-2 phosphorylation. 1109 80

Apoptosis or programmed cell death can be induced by a variety of stimuli including activation of death receptors. This subgroup of the TNF/NGF-receptor-superfamily activates caspases, a family of aspartyl-specific cysteine-proteases, which are the main executioners of apoptosis. Depending on the cell type, signalling pathways downstream of the death receptors can be modulated by different proteins such as Bcl-2, FLIPs, chaperones and kinases. Deregulation of apoptosis has been associated with diseases as cancer, autoimmunity and AIDS. Therefore, the identification of modulators of apoptosis has several therapeutic implications.
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PMID:Regulation of death receptor-mediated apoptosis pathways. 1113 52

Taxol-induced peripheral neuropathy is a commonly-occurring side-effect in the treatment of cancer patients with taxoteres or taxanes. Taxol is known to induce apoptosis in a number of tumor cells. This report documents that, similar to proliferating cells, taxol induces apoptosis in NGF-differentiated PC12 cells, as assessed by exogenous FITC-annexin-V binding and nuclear fragmentation. It is shown that PC12 cells that stably overexpress Bcl-2 are protected against the toxic effect of taxol, as evidenced by the XTT assay and by a decreased fraction of propididum iodide positive cells in a dye exclusion test. Also the number of annexin-V-positive cells and the number of fragmented nuclei are lower in the Bcl-2 transfected cells. The effect is similar to the protective effect of Bcl-2 against NGF deprivation in differentiated PC12 cells. Although taxol forced both wild-type and Bcl-2-overexpressing cells into a mitotic state, only in Bcl-2-overexpressing cells did this lead to the appearance of metabolically active, multi-nucleated cells. This suggests that Bcl-2 is able to induce an alternative escape pathway, downstream of the G2/M block, in taxol-treated differentiated PC12 cells.
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PMID:Bcl-2 protects neuronal cells against taxol-induced apoptosis by inducing multi-nucleation. 1122 15

Gene transfection and ectopic expression is a widely used method in experimental biology. In the present report, we would like to point out that this approach may, in certain circumstances, lead to a modification of the transfected cell phenotype. Indeed, we observed that after transfection of bcl-2 gene in the neuronal PC12 cell line some of the selected clones have lost their neuronal and catecholaminergic characteristics, i.e. TH expression and ability to grow neurites in response to NGF. Thus, the resistance of some PC12-Bcl-2 clones against neurotoxic insults may not necessarily reflect the potential benefit afforded by Bcl-2 expression. We therefore encouraged authors to verify cell phenotype after stable transfection to avoid misinterpretation of their results.
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PMID:A cautionary note on the use of stable transformed cells. 1123 39

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-kappaB (NFkappaB). We investigated the effect of NGF on the expression of Bcl-xL, an anti-apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.1-10 ng/ml) increased the expression of bcl-xL mRNA and protein. Reporter gene analysis revealed a significant increase in NFkappaB activity after treatment with NGF that was associated with increased nuclear translocation of the active NFkappaB p65 subunit. NGF-induced NFkappaB activity and Bcl-xL expression were inhibited in cells overexpressing the NFkappaB inhibitor, IkappaBalpha. Unlike tumor necrosis factor-alpha (TNF-alpha), however, NGF-induced NFkappaB activation occurred without significant degradation of IkappaBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein-tagged IkappaBalpha. Moreover, in contrast to TNF-alpha, NGF failed to phosphorylate IkappaBalpha at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of IkappaBalpha potently suppressed NFG-, but not TNF-alpha-induced NFkappaB activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-alpha-, but not NGF-induced NFkappaB activation. We conclude that NGF and TNF-alpha induce different signaling pathways in neurons to activate NFkappaB and bcl-x gene expression.
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PMID:Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha. 1126 66

By adulthood, sympathetic neurons have lost dependence on NGF and NT-3 and are able to survive in culture without added neurotrophic factors. To understand the molecular mechanisms that sustain adult neurons, we established low density, glial cell-free cultures of 12-wk rat superior cervical ganglion neurons and manipulated the function and/or expression of key proteins implicated in regulating cell survival. Pharmacological inhibition of PI 3-kinase with LY294002 or Wortmannin killed these neurons, as did dominant-negative Class IA PI 3-kinase, overexpression of Rukl (a natural inhibitor of Class IA PI 3-kinase), and dominant-negative Akt/PKB (a downstream effector of PI 3-kinase). Phospho-Akt was detectable in adult sympathetic neurons grown without neurotrophic factors and this was lost upon PI 3-kinase inhibition. The neurons died by a caspase-dependent mechanism after inhibition of PI 3-kinase, and were also killed by antisense Bcl-xL and antisense Bcl-2 or by overexpression of Bcl-xS, Bad, and Bax. These results demonstrate that PI 3-kinase/Akt signaling and the expression of antiapoptotic members of the Bcl-2 family are required to sustain the survival of adult sympathetic neurons.
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PMID:Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons. 1152 33

Infantile spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron (SMN)1 gene. We investigated the role of human (h) SMN protein on cell death in PC12 and Rat-1 cells. hSMN prolonged cell survival in PC12 cells deprived of trophic support and in Rat-1 cells induced to die by activation of the proto-oncogene c-Myc, to similar magnitude as Bcl-2 or IAP-2. While hSMN was ineffective in inhibiting apoptosis induced by ultraviolet light (UV) or etoposide treatment in proliferating PC12 or Rat-1 cells, a protective effect was observed in terminally NGF/dBcAMP-differentiated PC12 cells. hSMN inhibited the onset of apoptosis in NGF/dBcAMP-deprived or UV-treated co-differentiated PC12 cells by preventing cytochrome c release and caspase-3 activation, indicating that its effects are through suppression of the mitochondrial apoptotic pathway. Expressing hSMN deleted for exon 7 (Delta7) or for exons 6 and 7 (Delta6/7), or with the SMA point mutant Y272C, resulted in loss of survival function. Moreover, these mutants also exhibited pro-apoptotic effects in Rat-1 cells. The localization pattern of full-length hSMN in PC12 and Rat-1 cells was similar to that of endogenous SMN: granular labelling in the cytoplasm and discrete fluorescence spots in the nucleus, some of which co-localized with p80 coilin, the characteristic marker of Cajal bodies. However, cytoplasmic and nuclear aggregates were often seen with hSMNDelta7, whereas the hSMNDelta6/7 mutant showed homogenous nuclear labelling that excluded the nucleolus. Thus, our results show that the C-terminal region is critical in suppression of apoptosis by SMN.
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PMID:Involvement of survival motor neuron (SMN) protein in cell death. 1237 65

Bcl-2 is an antiapoptotic protein expressed in a wide variety of cell types. We have found that overexpression of bcl-2 in PC12 neural crest tumor cells leads to increased expression of neural differentiation-associated genes and decreased expression of proliferation-related genes. Culture growth rate decreases as well. Overexpression of bcl-2 also leads to increased expression of TrkA and increased phosphorylation of signal transductants in, albeit not specific for, the TrkA-MEK-ERK pathway. Blocking of NGF-mediated signaling through TrkA prevents Bcl-2-associated expression changes in differentiation-associated genes, raising the possibility that Bcl-2 mediates induction of neural differentiation through TrkA/NGF signaling.
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PMID:Bcl-2 mediates induction of neural differentiation. 1293 11

Recent studies have highlighted that female sex hormones represent potential neuroprotective agents against damage produced by acute and chronic injuries in the adult brain. Clinical reports have documented the effectiveness of estrogens to attenuate symptoms associated with Parkinson's disease, and to reduce the risk of Alzheimer's disease and cerebrovascular stroke. This evidence is corroborated by numerous experimental studies documenting the protective role of female sex hormones both in vitro and in vivo. Accordingly, estrogens have been shown to promote survival and differentiation of several neuronal populations maintained in culture, and to reduce cell death associated with excitotoxicity, oxidative stress, serum deprivation or exposure to beta-amyloid. The neuroprotective effects of estrogens have been widely documented in animal models of neurological disorders, such as Alzheimer's and Parkinson's diseases, as well as cerebral ischemia. Although estrogens are known to exert several direct effects on neurones, the cellular and molecular mechanisms implicated in their protective actions on the brain are not completely understood. Thus, on the basis of clinical and experimental evidence, in this review, we discuss recent findings concerning the neuronal effects of estrogens that may contribute to their neuroprotective actions. Both estrogen receptor-dependent and -independent mechanisms will be described. These include modulation of cell death regulators, such as Bcl-2, Akt and calpain, as well as interaction with growth factors, such as BDNF, NGF, IGF-I and their receptors. The anti-inflammatory effects of estrogens will also be described, namely their ability to reduce brain levels of inflammatory mediators, cytokines and chemokines. Finally, a brief overview about receptor-independent mechanisms of neuroprotection will aim at describing the antioxidant effects of estrogens, as well as their ability to modulate neurotransmission.
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PMID:From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens. 1596 77

The inappropriate expression/activation of cell-cycle-related molecules is associated with neuron death in many experimental paradigms and human neuropathologic conditions. However, the means whereby this links to the core apoptotic machinery in neurons have been unclear. Here, we show that the pro-apoptotic Bcl-2 homology 3 domain-only molecule Bcl-2 interacting mediator of cell death (Bim) is a target of a cell-cycle-related apoptotic pathway in neuronal cells. Induction of Bim in NGF-deprived cells requires expression and activity of cyclin-dependent kinase 4 (cdk4) and consequent de-repression of E2 promoter binding factor (E2F)-regulated genes including members of the myb transcription factor family. The Bim promoter contains two myb binding sites, mutation of which abolishes induction of a Bim promoter-driven reporter by NGF deprivation or E2F-dependent gene de-repression. NGF deprivation significantly increases endogenous levels of C-myb and its occupancy of the endogenous Bim promoter. These findings support a model in which apoptotic stimuli lead to cdk4 activation, consequent de-repression of E2F-regulated mybs, and induction of pro-apoptotic Bim.
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PMID:Bim is a direct target of a neuronal E2F-dependent apoptotic pathway. 1616 16


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