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)

We evaluated the cytotoxic effects of various human immunodeficiency virus (HIV-1) reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, stavudine, and nevirapine) on HIV-1-infected and uninfected T cell lines. Among the compounds, only stavudine (not the others) proved to be more cytotoxic to MOLT-4/IIIB cells (MOLT-4 cells chronically infected with HIV-1) than to uninfected MOLT-4 cells. Its 50% cytotoxic concentrations were 59.8 and 2.2 microM for MOLT-4 and MOLT-4/IIIB cells, respectively. Stavudine was also more cytotoxic to CEM/ROD (CEM cells chronically infected with HIV type 2) than to uninfected CEM cells. Microscopic analysis revealed that stavudine induced apoptosis in MOLT-4/IIIB cells. Apparent chromatin condensation in the nucleus was observed by electron microscopy. Furthermore, a DNA fragmentation ladder was detected by agarose gel electrophoresis. Addition of thymidine to the culture medium could rescue the cells from stavudine-induced apoptosis. The expression of anti-apoptotic protein Bcl-2 was partially downregulated in MOLT-4/IIIB cells after treatment with stavudine. This downregulation was not identified in MOLT-4 cells. These results indicate that stavudine selectively induces apoptosis in HIV-1-infected T cells and may have potential as a novel strategy for effective chemotherapy of the acquired immune deficiency syndrome (AIDS).
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PMID:Stavudine selectively induces apoptosis in HIV type 1-infected cells. 900 5

The effects of the expression of the human Bcl-2 family proteins Bax, Bak, Bcl-2, and Bcl-XL were examined in the fission yeast Schizosaccharomyces pombe and compared with Bax-induced cell death in mammalian cells. Expression of the proapoptotic proteins Bax and Bak conferred a lethal phenotype in this yeast, which was strongly suppressed by coexpression of the anti-apoptotic protein Bcl-XL. Bcl-2 also partially abrogated Bax-mediated cytotoxicity in S. pombe, whereas a mutant of Bcl-2 (Gly145Ala) that fails to heterodimerize with Bax or block apoptosis in mammalian cells was inactive. However, other features distinguished Bax- and Bak-induced death in S. pombe from animal cell apoptosis. Electron microscopic analysis of S. pombe cells dying in response to Bax or Bak expression demonstrated massive cytosolic vacuolization and multifocal nuclear chromatin condensation, thus distinguishing this form of cell death from the classical morphological features of apoptosis seen in animal cells. Unlike Bax-induced apoptosis in 293 cells that led to the induction of interleukin-1 beta-converting enzyme (ICE)/CED-3-like protease activity, Bax- and Bak-induced cell death in S. pombe was accompanied neither by internucleosomal DNA fragmentation nor by activation of proteases with specificities similar to the ICE/CED-3 family. In addition, the baculovirus protease inhibitor p35, which is a potent inhibitor of ICE/CED-3 family proteases and a blocker of apoptosis in animal cells, failed to prevent cell death induction by Bax or Bak in fission yeast, whereas p35 inhibited Bax-induced cell death in mammalian cells. Taken together, these findings suggest that Bcl-2 family proteins may retain an evolutionarily conserved ability to regulate cell survival and death but also indicate differences in the downstream events that are activated by overexpression of Bax or Bak in divergent cell types.
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PMID:Bax- and Bak-induced cell death in the fission yeast Schizosaccharomyces pombe. 919 Feb 11

We expressed the human anti-apoptotic protein, Bcl-2, in Saccharomyces cerevisiae to investigate its effects on antioxidant protection and stationary phase survival. Yeast lacking copper-zinc superoxide dismutase (sod1Delta) show a profound defect in entry into and survival during stationary phase even under conditions optimal for survival of wild-type strains (incubation in water after stationary phase is reached). Expression of Bcl-2 in the sod1Delta strain caused a large improvement in viability at entry into stationary phase, as well as increased resistance to 100% oxygen and increased catalase activity. In addition, Bcl-2 expression reduced mutation frequency in both wild-type and sod1Delta strains. In another set of experiments, wild-type yeast incubated in expired minimal medium instead of water lost viability quickly; expression of Bcl-2 significantly delayed this stationary phase death. Our results demonstrate that Bcl-2 has activities in yeast that are similar to activities it is known to possess in mammalian cells: (a) stimulation of antioxidant protection and (b) delay of processes leading to cell death.
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PMID:Human Bcl-2 reverses survival defects in yeast lacking superoxide dismutase and delays death of wild-type yeast. 919 72

Expression of the Fas 'death receptor', Fas (CD95/APO-1) renders cells susceptible to programmed cell death ('apoptosis'), whereas Bcl-2 protects cells from apoptosis. Using fluorescence immunohistochemistry, we analysed Fas and Bcl-2 expression in muscle from five patients with polymyositis (PM), four patients with inclusion body myositis (IBM), three patients with dermatomyositis (DM), three patients with Duchenne muscular dystrophy (DMD) and three nonmyopathic controls. Fas (CD95) and Bcl-2 were not detected in control muscle, but expressed in muscle fibres and inflammatory cells in PM, IBM, DM and DMD. The proportion of Fas+ muscle fibres ranged from < 1 to 50%, and was higher in PM and IBM than in DM and DMD. On average, the Fas+ muscle fibres were smaller (median diameter, 10 microns; range, 7-32 microns) than the Fas- fibres (median, 36 microns; range, 10-60 microns). Less than 10% of the Fas+ muscle fibres co-expressed the regeneration marker CD56 (neural cell adhesion molecule N-CAM). In PM and IBM, the proportion of Fas+ muscle fibres was higher among fibres invaded or contacted by T cells than among fibres not contacted by T cells (P < 0.01). The proportion of Fas+ fibres co-expressing Bcl-2 was 76 +/- 16% in PM, 100% in IBM and 63 +/- 23% in DM. Fas and Bcl-2 expression was also noted in inflammatory cells in PM, IBM, DM and DMD. Using the terminal deoxytransferase-catalysed DNA nick end labelling technique for detection of nuclear DNA fragmentation, none of myonuclei, and < 0.1% of inflammatory cell nuclei, showed signs of apoptosis. Our results suggest that, although Fas expression confers susceptibility to Fas-mediated apoptosis, Fas-expressing muscle fibres and inflammatory cells are protected by the anti-apoptotic protein Bcl-2.
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PMID:Cytotoxic mechanisms in inflammatory myopathies. Co-expression of Fas and protective Bcl-2 in muscle fibres and inflammatory cells. 921 78

We report a pilot study on the Fas receptor (APO-1, CD95) in vivo in 15 human squamous cell (non-small) carcinomas and ten normal bronchial specimens. The principal aim was to investigate whether the so-called death receptor, Fas, is present in these tumours. Ligation of Fas promptly induces apoptosis, particularly in T Jurkat cells in vitro, and expression of Fas on human cancer would thus theoretically be of great interest. The immunoreactivity for the anti-apoptotic protein Bcl-2 was also investigated, and the degree of apoptosis was evaluated by TdT dUTP nick end labelling (TUNEL) and conventional morphological criteria. Fas was present in all initial tumours but absent in control tissue, that is in the potential precursor cells of bronchial epithelium (P = 0.001). Fas was not detectable after radiotherapy (P = 0.03). We propose that radiotherapy induces an early selection of tumour cells rather than a down-regulation of Fas. Both Bcl-2 and apoptosis (TUNEL) were generally expressed at a modest level. In agreement with other studies, we did not find any significant correlation between Bcl-2 and prognosis, or between Bcl-2 and TUNEL. Hence, in this preliminary report, we have demonstrated Fas receptor in human squamous cell carcinomas in vivo. This is a novel finding, and the apparent absence of Fas after radiotherapy may have important therapeutic implications.
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PMID:Fas receptor is expressed in human lung squamous cell carcinomas, whereas bcl-2 and apoptosis are not pronounced: a preliminary report. 923 16

It is generally accepted that suppression of apoptosis in chemically initiated hepatocytes results in promotion of rodent hepatocarcinogenesis. Using immuno-histochemical methods, I studied the expression of Bcl-2, an anti-apoptotic protein, in hepatocellular tumors of B6C3F1 mice. Although normal mouse hepatocytes did not express detectable amounts of Bcl-2, most diethylnitrosamine-induced tumors were positive for this protein. Virtually all of the Bcl-2-positive tumors were composed of small basophilic hepatocytes, whereas the rare cases of Bcl-2-negative tumors demonstrated an eosinophilic appearance. To confirm this difference, tumors initiated with diethylnitrosamine and promoted by phenobarbital were also studied, as this initiation-promotion protocol has been shown to selectively produce eosinophilic lesions. All such tumors were immunohistochemically negative for Bcl-2. The relatively infrequent basophilic tumors found with phenobarbital treatment, however, did express Bcl-2. Thus, the concordance with basophilia was observed regardless of the nature of the promotion agent. These results indicate that the two types of tumors are qualitatively distinct and may develop through independent mechanisms.
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PMID:Correlation between Bcl-2 expression and histopathology in diethylnitrosamine-induced mouse hepatocellular tumors. 932 29

Apoptosis and oxidative stress have been suggested to be involved in Parkinson's disease (PD). However, whether this is a cause or consequence of neurodegeneration is unknown. Incidental Lewy Body disease (ILBD) appears to be a presymptomatic form of Parkinson's disease where individuals are neurologically normal, but after post-mortem examination pathology similar to Parkinson's disease is present. Thus, ILBD can be used to examine the early stages of the pathological process in PD. We investigated the levels of Bcl-2, an anti-apoptotic protein known to decrease cell death induced by several mechanisms, including oxidative stress. Our data show that Bcl-2 is significantly raised in the basal ganglia regions of PD patients as compared to age-matched controls. A similar trend is also found in ILBD. We propose that Bcl-2 increases in some brain regions as an early event and that these brain regions are under a stress for perhaps many years before any symptomatic changes occur.
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PMID:Upregulation of the anti-apoptotic protein Bcl-2 may be an early event in neurodegeneration: studies on Parkinson's and incidental Lewy body disease. 936 87

Spinal muscular atrophy (SMA) is a motor neuron disease characterized by degeneration of the anterior horn cells of the spinal cord. It is a common fatal autosomal recessive disorder and linkage studies have identified two candidate genes, SMN and NAIP, both on chromosome 5q13. Although NAIP protein is known to have an anti-apoptotic function, the function of SMN has been unclear and it shows no significant sequence similarity to any other protein. The SMN gene is deleted or interrupted on both chromosomes in nearly all SMA patients. Here we show that SMN interacts with Bcl-2, another anti-apoptotic protein, and that co-expression of SMN with Bcl-2 confers a synergistic preventive effect against Bax-induced or Fas-mediated apoptosis, although SMN itself has only a weak anti-apoptotic activity. SMN(Y272C), which carries a missense mutation and was found in an SMA patient who exceptionally retained SMN on one allele, exerts no synergism with Bcl-2. Furthermore, the product of a truncated transcript lacking exon 7, which was derived from an SMN gene carrying an intragenic mutation or from the SMN copy gene cBCD541 retained in all SMA patients, had no synergistic activity but instead had a dominant-negative effect on full-length SMN. Our results indicate that an absent or decreased anti-apoptotic activity of SMN in concert with Bcl-2 underlies the pathogenesis of SMA.
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PMID:Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy. 938 83

The pro-apoptotic protein Bax can homodimerize with itself and heterodimerize with the anti-apoptotic protein Bcl-2, but the significance of these protein-protein interactions remains unclear. Alanine substitution mutations were created in a well conserved IGDE motif found within the BH3 domain of Bax (residues 66-69) and the resulting mutant Bax proteins were tested for ability to homodimerize with themselves and to heterodimerize with Bcl-2. Correlations were made with cell death induction by these mutants of Bax both in mammalian cells where Bax may function through several mechanisms, and in yeast where Bax may exert its lethal actions through a more limited repertoire of mechanisms perhaps related to its ability to form ion channels in intracellular membranes. Two of the mutants, Bax(D68A) and Bax(E69A), retained the ability to homodimerize but failed to interact with Bcl-2 as determined by yeast two-hybrid assays and co-immunoprecipitation analysis using transfected mammalian cells. The Bax(E69A) protein exhibited a lethal phenotype in yeast, which could be specifically suppressed by co-expression of Bcl-2, despite its failure to dimerize with Bcl-2. Both the Bax(D68A) and Bax(E69A) proteins induced apoptosis when overexpressed in human 293 cells, despite an inability to bind to Bcl-2. Moreover, co-expression of Bcl-2 with Bax(D68A) and Bax(E69A) rescued mammalian cells from apoptosis. In contrast, a mutant of Bax lacking the IGDE motif, Bax(DeltaIGDE), was incapable of either homodimerizing with itself or heterodimerizing with Bcl-2 and was inactive at promoting cell death in either yeast or mammalian cells. Although failing to interact with Bcl-2, the Bax(D68A) and Bax(E69A) mutants retained the ability to bind to Bid, a putative Bax-activating member of the Bcl-2 family, and collaborated with Bid in inducing apoptosis. When taken together with previous observations, these findings indicate that (i) Bax can induce apoptosis in mammalian cells irrespective of heterodimerization with Bcl-2 and (ii) Bcl-2 can rescue both mammalian cells and yeast from the lethal effects of Bax without heterodimerizing with it. However, these results do not exclude the possibility that BH3-dependent homodimerization of Bax or interactions with Bax activators such as Bid may either assist or be required for the cell death-inducing mechanism of this protein.
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PMID:Heterodimerization-independent functions of cell death regulatory proteins Bax and Bcl-2 in yeast and mammalian cells. 939 83

Bcl-2 is a major anti-apoptotic protein expressed in many normal and malignant cells. Recently, low to absent expression was reported in human natural killer (NK) cells cultured in serum-free media which could be induced with stem cell factor. We investigated the expression of bcl-2 protein of NK cells in normal blood donors and compared the bcl-2 expression in CD56+ NK cells with CD3+ T cells. To determine bcl-2 reactivity, a three-color flow-cytometric technique was used. CD56+ CD3- NK cells had an average bcl-2 expression of 83% compared with CD3+ T cells. CD56 and CD3 double positive T cells had an average content of 111% compared with all peripheral CD3+ T lymphocytes. When peripheral mononuclear cells were cultured with interleukin-2 (IL-2), bcl-2 could be upregulated by IL-2 in all cell populations studied. The induction of bcl-2 in these cell populations paralleled the induction in CD56- T lymphocytes cultured under identical conditions. The induction of bcl-2 by IL-2 was confirmed by Western blotting. The maximum induction of bcl-2 by IL-2 was observed at an IL-2 dose of 100-1,000 U/ml. Our data confirm the anti-apoptotic protein bcl-2 as an activation- or proliferation-associated marker of normal NK cells which can be induced by IL-2.
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PMID:Bcl-2 is expressed in human natural killer cells and is regulated by interleukin-2. 952 82


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