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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 26-kDa protein encoded by the bcl-2 gene is a regulator of cell survival and blocks cell death induced by numerous stimuli. Amyloid beta protein (ABP) and glutamate are believed to play important roles in the neuronal cell death that occurs in Alzheimer's disease and stroke, respectively. Glutamate induces apoptosis in some neuronal cell systems, but it remains controversial whether ABP-mediated cell death occurs through apoptosis or necrosis. To further explore the pathways for cell death that are activated by these neurotoxins, we examined the effects of elevated levels of the p26-Bcl-2 protein on the susceptibility of neuronal cell lines to killing by glutamate and ABP. Gene transfer methods were used to elevate p26-Bcl-2 protein levels in the rat nerve lines PC-12 and B50 and the human neuroblastoma IMR-5. Bcl-2 protected all 3 cell lines from glutamate induced cell death but had no effect on killing mediated by ABP.
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PMID:BCL-2 prevents killing of neuronal cells by glutamate but not by amyloid beta protein. 790 32

1. Over 100 different agents have been shown, under certain circumstances, to cause apoptosis, a form of cell death with characteristic morphology. In most cases, the mechanism of cell death is likely to be the same, as expression of the cell death inhibitory gene bcl-2 can frequently prevent apoptotic changes and/or delay cell death. 2. These observations raise the question of how and why cells detect these agents and why they respond by implementing the suicide mechanism that bcl-2 can control. Our hypothesis is that apoptosis is used as an anti-viral strategy, and that cells interpret any metabolic disturbance as evidence of infection by a virus and thereby kill themselves in response to these toxins before they are killed by the action of the toxin itself. 3. Experiments on the effect of sodium azide upon growth factor-dependent cells support this idea. Bcl-2 can delay cell death caused by azide, and inhibit apoptotic changes seen by electron microscopy, but cannot prevent the eventual death of the cells. 4. These ideas suggest that drugs designed to regulate cell death may be useful for the treatment of ischaemic or neoplastic diseases. For example, human cells may activate a suicide pathway in response to sub-lethal amounts of anoxia following a stroke or heart attack and so blocking apoptosis may be a useful therapy to limit tissue damage. On the other hand, increasing the propensity of cells to activate their physiological cell death mechanisms may enhance the effectiveness of toxins designed to kill tumour cells.
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PMID:Hypothesis: apoptosis caused by cytotoxins represents a defensive response that evolved to combat intracellular pathogens. 859 45

Extensive neuronal death occurs in the developing nervous system. Death of neurons during this process is apoptotic and appears to utilize a pathway that is conserved in various mammalian cells and organisms. Recent evidence suggests that neuronal death during trauma, stroke, or neurodegenerative diseases may also occur by a similar mechanism. This review discusses the molecular mechanism of developmental neuronal death by examining the biochemical and molecular events associated with neuronal death after trophic factor withdrawal. The ability to inhibit neuronal death by manipulating the Bcl-2 or the ICE-family proteins demonstrates the importance of these proteins in the neuronal apoptotic pathway. The utility of inhibiting neuronal death by blocking the apoptotic pathway as therapy in neuropathological situations is discussed.
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PMID:Neuronal death in developmental models: possible implications in neuropathology. 894 13

Recent studies indicate that the proto-oncogene Bax, and other related proteins (eg Bcl-2) may play a major role in determining whether cells will undergo apoptosis under conditions which promote cell death. Increased expression of Bax has been found to promote apoptosis, while over-expression of Bcl-2 can inhibit apoptosis. To investigate the role of Bax in nerve cell death in the rat brain we examined the level of Bax expression in cells undergoing apoptosis, using a hypoxic-ischemic stroke model. We found that Bax was expressed at high levels in the nuclei of neurons in the hippocampus, cortex, cerebellum, and striatum on the control side, and that Bax levels increased in hippocampal neurons undergoing apoptosis on the stroke side, and then declined (correlating with cell loss). In the Alzheimer's disease hippocampi we found a concentrated localisation of Bax in senile plaques, which correlated with the localisation of beta-amyloid protein in adjacent sections from the same brains. beta-Amyloid positive plaques are thought to contribute to the Alzheimer's disease process, possibly via an apoptotic mechanism, and this may occur via an increase in Bax in these areas. Bax was also strongly stained in tau-positive tangles in Alzheimer's disease hippocampi, suggesting Bax may play a role in tangle formation. In addition, we observed a loss of Bax expression in the dentate granule cells of Alzheimer's disease hippocampi compared with moderate Bax expression in control hippocampi, and this loss may be related to the survival of these neurons in Alzheimer's disease. Finally, we observed substantially different staining patterns of Bax using three different commercially available antisera to Bax, indicating the need for caution when interpreting results in this area.
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PMID:Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. 909 48

Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.
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PMID:Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. 926 33

Programmed cell death contributes to the morbidity and mortality of several neurological disorders including stroke, Alzheimer's disease and human immunodeficiency virus (HIV)-associated dementia. Patients with HIV dementia show evidence of programmed cell death in brain. In vitro data demonstrates several neurotoxic products of macrophage infection that cause neural cell death, including tumor necrosis factor alpha (TNFalpha) and platelet activating factor (PAF). We treated human brain aggregate cultures with these cytokines and determined their effect on the mRNA and protein levels for Bcl-2, Bcl(x) and Bax alpha. TNFalpha and PAF differentially regulate the Bcl-2 family of proteins at a post-transcriptional level. Following TNFalpha treatment, Bcl-2 protein is significantly decreased, and at least one additional Bax isomer emerges. Bcl(xL) protein is slightly increased after treatment with either cytokine. We demonstrated that overexpression of Bcl-2 in brain aggregate cultures protects cells from TNFalpha-induced damage but has no effect on cell damage induced by PAF. We conclude that Bcl-2 and Bax alpha proteins play significant roles in modulating neural cell death from TNFalpha- but not from PAF-induced cell damage.
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PMID:Differential modulation of cell death proteins in human brain cells by tumor necrosis factor alpha and platelet activating factor. 982 63

This overviews recent understanding of the mechanisms of apoptosis on ischemia-induced neuronal cell death. Apoptosis is a prominent feature of the developing nervous system. Several lines of evidence suggest that apoptosis is also an important mechanism of cell death in adult brain in acute or chronic diseases such as stroke and Alzheimer's disease. In animal models of stroke, markers of apoptosis such as cytoplasmic and nuclear condensation and DNA fragmentation appear in neurons. A variety of physiological and pathological stimuli can activate signal-transduction pathways that result in the sequential proteolytic activation of caspase family members. The activation of caspases can be inhibited by several molecules, including peptide aldehydes (caspase-1 and or caspase-3 inhibitors) and crmA that target the active-site cysteine of caspase family members, Bcl-2, IAP (inhibitor of apoptosis protein) and NAIP (neuronal apoptosis inhibitory protein). Once activated, caspase-1 protease can activate the caspase family members and hydrolyze a discrete set of cellular targets. Poly (ADP-ribose)polymerase (PARP), which appears to facilitate apoptosis, was recognized as a substrate of activated caspase-3. These results suggest that caspase family, bcl-2 family, IAP family and substrates such PARP contribute to mechanisms of cell death in ischemic brain injury. Inhibition of the caspase family, particularly by non-peptide inhibitors that cross the blood-brain barrier and easily penetrate neurons and glia, could provide novel treatments for stroke and other forms of brain and spinal cord injury in humans.
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PMID:[Involvement of caspase on apoptosis in ischemia-induced neuronal cell death: usefulness of caspase inhibitors for stroke therapy]. 1020 84

Protective effects after focal cerebral ischemia were assessed in transgenic mice that overexpress in a neuron-specific fashion mouse Bcl-XL or human Bcl-2. Both Bcl genes were under the control of the same mouse Thy-1 regulatory sequences resulting in very similar expression patterns in cortical neurons. Furthermore, these sequences direct lateonset (i.e. around birth) expression in brain, thus minimizing effects of transgene expression during brain development. Effects on infarct volume were measured using MRI after permanent occlusion of the middle cerebral artery (MCA). When compared to their non-transgenic littermates, Thy1mbcl-XL mice showed a significant 21% reduction in infarct size whereas Thy1hbcl-2 mice did not reveal any reduction. These findings suggest a selective protective advantage of Bcl-XL as compared with Bcl-2 in this mouse model for human stroke.
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PMID:Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice. 1040 19

Calcineurin is a Ca(2+)/calmodulin-dependent protein phosphatase that is abundantly expressed in several specific areas of the brain, which are exceptionally vulnerable to stroke, epilepsy, and neurodegenerative diseases. In this study, we assessed the effects of high level activity of calcineurin on neuronal cells. Virus-mediated high level constitutive activity of calcineurin rendered neuronal cells susceptible to apoptosis induced by serum reduction or by a brief exposure to calcium ionophore. Adenovirus-mediated, high level forced activity of calcineurin induced cytochrome c/caspase-3-dependent apoptosis in neurons. Preincubation with the calcineurin inhibitors cyclosporin A and FK506 reduced susceptibility to apoptosis. High level constitutive expression of Bcl-2 or CrmA or incubation with a specific caspase-3 inhibitor inhibited the calcineurin-induced apoptosis. These data indicate that high level constitutive activity of calcineurin predisposes neuronal cells to cytochrome c/caspase-3 dependent apoptosis even under sublethal conditions.
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PMID:High level calcineurin activity predisposes neuronal cells to apoptosis. 1056 26

Bax-mediated apoptosis in neurons is involved in many pathologic conditions affecting the central nervous system, including degenerative diseases, stroke, and trauma. Two molecules belonging to the Bcl-2 family, Bcl-2 and Bcl-X(L), protect cells from Bax-induced apoptosis and show distinct expression patterns in adult neurons, with downregulated Bcl-2 and highly upregulated Bcl-X(L) expression. To investigate the biological functions of these two molecules in Bax-mediated apoptosis in neurons, we transduced various levels of Bcl-X(L) or Bcl-2 via adenoviral vectors into nerve growth factor (NGF)-treated PC12 cells. Overexpression of Bax induced drastic apoptosis in NGF-treated PC12 cells. Bcl-X(L) expressed at a wide range of levels conferred a high level of protection against Bax-mediated apoptosis. In contrast, Bcl-2 at various levels conferred far less protection against apoptosis. Moreover, Bcl-X(L) protected PC12 cells from apoptosis induced by NGF withdrawal. These data indicate that Bcl-X(L)-mediated protection is the major pathway that suppresses apoptosis in NGF-treated PC12 cells and that Bcl-X(L) would be a more relevant target of manipulation in future treatment strategies, including gene therapies.
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PMID:Adenovirus-mediated transfer of Bcl-X(L) protects neuronal cells from Bax-induced apoptosis. 1064 Apr 20


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