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

Cells undergo apoptosis in response to a wide range of stimuli, and this response may represent an ancient defence mechanism against pathogens. Bcl-2 is able to prevent apoptosis in many cases. Although blocking cell suicide is not directly oncogenic, enforced bcl-2 expression can lead to cancer by lengthening the life-span of cells, during which time secondary changes, such as activation of additional oncogenes like c-myc, can occur. Bcl-2 cannot block apoptosis of target cells by cytotoxic T lymphocytes. Thus cytotoxic T cells are able to fight viruses that carry anti-apoptosis genes that resemble bcl-2. Genes involved in the regulation of mammalian apoptosis are similar to those that mediate programmed cell death in C. elegans. By studying cell death genes in viruses and worms as well as mammals, we will learn more about this fascinating process.
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PMID:Analysis of the role of bcl-2 in apoptosis. 769 91

Cells are eliminated in a variety of physiological settings by apoptosis, a genetically encoded process of cellular suicide. Apoptosis comprises an intrinsic cellular defence against tumorigenesis, which, when suppressed, may contribute to the development of malignancies. The bcl-2 oncogene, which is activated in follicular lymphomas, functions as a potent suppressor of apoptosis under diverse conditions. Here we describe the complementary DNA cloning and functional analysis of a new Bcl-2 homologue, Bak, which promotes cell death and counteracts the protection from apoptosis provided by Bcl-2. Moreover, enforced expression of Bak induces rapid and extensive apoptosis of serum-deprived fibroblasts. This raises the possibility that Bak is directly involved in activating the cell death machinery.
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PMID:Induction of apoptosis by the Bcl-2 homologue Bak. 771 30

A novel oncogene-derived protein, Bcl-2, functions as a repressor of cell death in a genetic pathway of cellular suicide that appears to be common to all multicellular animals. A related protein that promotes cell death, Bax, wrestles with Bcl-2 through conserved motifs, BH1 and BH2, establishing a set point for these deaths. In Bcl-2-deficient mice, the ratio of these molecules is reset, resulting in massive cell death in several cell types.
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PMID:Regulators of cell death. 773 71

Whether a cell decides to proliferate, undergo growth arrest, or even commit suicide is determined by a multitude of highly potent positive and negative regulatory factors. Mutational perturbation of these factors and the normal pathways through which they regulate either cell proliferation or cell death can induce a pathologic enhancement in cell number, or hyperplasia, and eventually the development of malignant tumors. Serving as valuable animal models for cancer in humans, transgenic mice have been used to demonstrate the dramatic consequences of subverting the normal molecular mechanisms regulating cell proliferation and/or cell death. This review will use three transgenic mouse models to illustrate the consequences of inducing such regulatory imbalances, as well as the utility and versatility of the transgenic approach in cancer research. Three different regulatory factors are considered; transforming growth factor-alpha is discussed as an example of a positive growth regulator, p53 as a negative growth regulator, and Bcl-2 as an inhibitor of programmed cell death.
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PMID:Regulatory imbalances in cell proliferation and cell death during oncogenesis in transgenic mice. 818 84

In this paper the specific mitochondrial respiratory chain inhibitors rotenone and antimycin A and the highly specific mitochondrial ATP-synthase inhibitor oligomycin are shown to induce an apoptotic suicide response in cultured human lymphoblastoid and other mammalian cells within 12-18 h. The mitochondrial inhibitors do not induce apoptosis in cells depleted of mitochondrial DNA and thus lacking an intact mitochondrial respiratory chain. Apoptosis induced by respiratory chain inhibitors is not inhibited by the presence of Bcl-2. We discuss the possible role of mitochondrial induced apoptosis in the ageing process and age-associated diseases.
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PMID:Mitochondrial respiratory chain inhibitors induce apoptosis. 831 78

Transformation of primary rodent cells by the adenovirus E1A and E1B oncogenes is a two-step process, where E1A-dependent induction of proliferation is coupled to E1B-dependent suppression of programmed cell death (apoptosis). The E1B gene encodes two distinct transforming proteins, the 19K and 55K proteins, both of which independently cooperate with E1A. E1B 19K or 55K protein, or the human Bcl-2 protein, functions to suppress apoptosis and thereby permits transformation with E1A. The E1B 55K protein blocks p53 tumor suppressor protein function, indicating that p53 may mediate apoptosis by E1A. In the mutant conformation, p53 blocked induction of apoptosis by E1A and efficiently cooperated with E1A to transform primary cells. When p53 was returned to the wild-type conformation, E1A+p53 transformants underwent cell death by apoptosis. This induction of apoptosis by conformational shift of p53 from the mutant to the wild-type form was inhibited by expression of the E1B 19K protein. Thus, the p53 protein may function as a tumor suppressor by initiating a cell suicide response to deregulation of growth control by E1A. E1B 19K and 55K proteins provide separate mechanisms that disable the cell suicide pathway of p53.
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PMID:Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. 838 80

Programmed cell death in the myocardium has been linked to ischemia reperfusion injury as well as to excessive mechanical forces associated with increases in ventricular loading. Moreover, hypoxia activates the suicide program of cardiac myocytes in vitro. Because the supplied portion of the ventricular wall is ischemic and subjected to high levels of systolic and diastolic stresses (acutely after coronary artery occlusion), apoptosis and necrosis may contribute independently to myocyte cell death after infarction. Therefore, myocardial infarction was produced in rats, and, after the determination of ventricular hemodynamics, the contribution of apoptotic and/or necrotic myocyte cell death to infarct size was measured quantitatively from 20 minutes to 7 days after coronary artery occlusion. Programmed cell death was assessed by the terminal deoxynucleotidyl transferase assay and by the electrophoretic detection of DNA laddering. Myocyte necrosis was evaluated by myosin monoclonal Ab labeling. Moreover, the expression of Bcl-2, Bax, and Fas proteins in myocytes was examined by immunocytochemistry. Myocyte cell death by apoptosis and necrosis comprised nearly 3 million myocytes at 2 hours. Apoptotic cell death involved 2.8 million cells and necrotic cell death only 90,000 myocytes. Apoptosis continued to represent the major independent form of myocyte cell death, affecting 6.6 million myocytes at 4.5 hours. Myocyte necrosis peaked at 1 day, including 1.1 million myocytes. DNA electrophoretic analysis confirmed these observations by showing nucleosomal ladders at 2-3 hours, 4.5 hours, 1 day, and 2 days after coronary artery occlusion. Myocytes showing both DNA strand breaks and myosin labeling were a prominent aspect of myocardial damage only after 6 hours. Finally, the expression of Bcl-2 and Fas in myocytes increased 18-fold and 131-fold, respectively. In conclusion, programmed myocyte cell death is the major form of myocardial damage produced by occlusion of a major epicardial coronary artery, whereas necrotic myocyte cell death follows apoptosis and contributes to the progressive loss of cells with time after infarction. The enhanced expression of Fas may be implicated in the activation of apoptosis in spite of the increase in Bcl-2, which tends to preserve cell survival.
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PMID:Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. 856 1

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

Programmed cell death (apoptosis) plays a major role in embryogenesis, in mature organ homeostasis and in many disease states including cancer. Apoptosis occurs as an orderly cell-intrinsic suicide program regulated by a family of genes related to Bcl-2. Here, we describe the cloning and molecular characterization of a gene homologous to Bcl-2 from a human glioma. This gene named BRAG-1 (for brain-related apoptosis gene) has an open reading frame that encodes for a protein of 31 kDa sharing significant sequence homology with the Bcl-2 family of genes in the BH1 and BH2 regions. Northern blot analyses revealed that BRAG-1 is expressed in human gliomas as a 1.8 kb message. This gene, interestingly, was found to be expressed predominantly in normal human brain as a 4.5 kb transcript which is different in size from the message found in tumor tissues. These results suggest that BRAG-1 may be rearranged in human gliomas leading to its over-expression as a truncated transcript. Utilizing a bacterial expression vector, we produced BRAG-1 protein which was found to cross-react with a Bcl-2 monoclonal antibody, further suggesting structural and immunological similarity to Bcl-2.
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PMID:Identification of a novel Bcl-2 related gene, BRAG-1, in human glioma. 864 11

Apoptosis is a form of programmed cell death that occurs under numerous developmental and physiological conditions that require the selective elimination of cells from tissues and organs without the production of an inflammatory response. The initiation of apoptosis is controlled by a regulation of the balance between death and life signals perceived by the cell. A typical response of cells to an apoptotic stimulus includes a reduction in cell volume, compaction of intracellular organelles, chromatin condensation, and the generation of apoptotic bodies which contain degraded cellular components. Apoptotic bodies are often engulfed by neighboring cells or macrophages, preventing the occurrence of an inflammatory response in the region of the dying cells. Although the molecular basis for this cellular suicide is poorly understood, evidence indicates that apoptosis is an active process, requiring energy for its effective completion. We have sought to define the catabolic "effector" molecules that carry out the apoptotic process using glucocorticoid-induced apoptosis in rodent and human lymphocytes as model systems. These cells respond to dexamethasone with an arrest of cell growth, chromatin condensation, cell shrinkage, and the selective degradation of DNA, RNA, and protein. These effects are dependent on the presence of functional glucocorticoid receptors and require gene expression. The fragmentation of DNA and its associated cell shrinkage has been a focus of our efforts, because these effects reflect an irreversible commitment to death. Accordingly, we have developed assays to study apoptosis at the single cell level and to identify, purify, and clone the nuclease(s) that cause DNA damage in apoptotic cells. Using these approaches, we have identified and characterized a novel low molecular weight nuclease (NUC18) whose activity correlates with the DNA degradation occurring during apoptosis. NUC18 requires calcium for optimal activity in vitro and is inhibited by zinc and aurintricarboxylic acid, two known inhibitors of apoptosis. The amino acid sequence of pure NUC18 reveals a surprising homology to the cyclophilin family of proteins. Furthermore, recombinant cyclophilins have biochemical and pharmacological properties identical to those of NUC18. We have also studied the molecular basis for the catabolism of RNA and proteins that occurs during lymphocyte apoptosis. Recent experiments have identified selective cleavage of 28S ribosomal RNA and a novel nonlysosomal protease, both of which contribute to the demise of the cell. In summary, we present an evolving model that unifies the activation of apoptosis in lymphocytes by glucocorticoids with the counter-balancing effect of inhibitors such as Bcl-2.
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PMID:The biochemistry and molecular biology of glucocorticoid-induced apoptosis in the immune system. 870 Oct 91


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