UNIPROT:P10415 - FACTA Search

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

An ability of the Epstein-Barr virus latent membrane protein LMP1 to enhance the survival of infected B cells through upregulation of the bcl-2 oncogene was first suggested by experiments involving gene transfection and the selection of stable LMP1+ clones (S. Henderson, M. Rowe, C. Gregory, F. Wang, E. Kieff, and A. Rickinson, Cell 65:1107-1115, 1991). However, it was not possible to ascertain whether Bcl-2 upregulation was a specific consequence of LMP1 expression or an artifact of the selection procedure whereby rare Bcl-2+ cells already present in the starting population might best be able to tolerate the potentially toxic effects of LMP1. We therefore reexamined this issue by using two different experimental approaches that allowed LMP1-induced effects to be monitored immediately following expression of the viral protein and in the absence of selective pressures; activation of the NF-kappa B transcription factor and upregulation of the cell adhesion molecule ICAM-1 were used as early indices of LMP1 function. In the first approach, stable clones of two B-cell lines carrying an LMP1 gene under the control of an inducible metallothionein promoter were induced to express LMP1 in all cells. Activation of NK-kappa B and upregulation of ICAM-1 occurred within 24 h and were followed at 48 to 72 h by upregulation of Bcl-2. In the second approach, we tested the generality of this phenomenon by transiently expressing LMP1 from a strong constitutively active promoter in a range of different cell types. All six B-cell lines tested showed NF-kappa B activation in response to LMP1 expression, and this was followed in five of six lines by expression of ICAM-1 and Bcl-2. In the same experiments, all three non-B-cell lines showed NF-kappa B activation and ICAM-1 upregulation but never any effect upon Bcl-2. We therefore conclude that Bcl-2 upregulation is part of the panoply of cellular changes induced by LMP1 but that the effect is cell type specific. Our data also suggest that whilst NF-kappa B may be an essential component of LMP1 signal transduction, other cell-specific factors may be required to effect some functions of the viral protein.
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PMID:Upregulation of bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell-specific response that is delayed relative to NF-kappa B activation and to induction of cell surface markers. 752 93

It has been generally accepted that inhibition of apoptosis is important in the development of malignancy. To determine whether Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), the virus-coded transforming oncogene product, has an anti-apoptotic function in non-B-cells, Jurkat T cells were transfected with the LMP1-expression vector pSV2gptMTLM consisting of the human metallothionein promoter and were selected for mycophonolic acid resistance. LMP1-expressing clones of Jurkat cells showed resistance to apoptosis induced by serum deprivation. In LMP1-expressing clones, although the levels of Bcl-2 and Bax were similar to those in the clones of vector transfectants or parental cells, c-Myc expression was significantly depressed. Down-regulation of c-Myc by LMP1 was confirmed by using LMP1-expressing clones treated with CdCl2. Addition of c-myc antisense oligonucleotides to Jurkat cells specifically inhibited apoptosis induced by serum deprivation at the concentrations which suppressed c-Myc expression. These results suggest that LMP1 expression and subsequent down-regulation of c-Myc protect Jurkat T cells from apoptosis induced by serum deprivation. The significance of the anti-apoptotic function of LMP1 in non-B, Jurkat T cells is discussed in relation to the pathogenesis of EBV malignancy.
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PMID:Expression of Epstein-Barr virus latent membrane protein 1 protects Jurkat T cells from apoptosis induced by serum deprivation. 912 31

Our group recently reported that cultured sheep pulmonary artery endothelial cells (SPAECs) became resistant to lipopolysaccharide (LPS)-induced apoptosis several days after constitutive synthesis of nitric oxide (NO) after adenoviral (Ad) transfer of inducible NO synthase (iNOS) or exposure to the NO donor S-nitroso-N-acetylpenicillamine (SNAP) (E. Tzeng, Y.-M. Kim, B. R. Pitt, A. Lizonova, I. Kovesdi, and T. R. Billiar. Surgery 122: 255-263, 1997). In the present study, we confirmed this observation by establishing stable transfectants after retroviral gene transfer [replication-deficient retrovirus (DFG)] of human iNOS (DFG-iNOS) SPAECs and then used all three approaches (Ad, DFG, and SNAP) to determine underlying mechanisms of this phenomenon. Continuous endogenous production of NO in itself did not cause apoptosis as assessed by phase-contrast microscopy, nuclear morphology, and internucleosomal DNA fragmentation. Prolonged (72-96 h) synthesis of NO, however, after DFG- or replication-deficient adenovirus (Ad. CMV)-iNOS or SNAP (100 microM, 96 h) inhibited LPS-induced apoptosis. The kinetics of such protection suggested that NO may be inducing other gene products. Ad-mediated transfer of manganese superoxide dismutase (MnSOD) decreased the sensitivity of wild-type SPAECs to LPS-induced apoptosis. MnSOD, however, was not induced in an NG-monomethyl-L-arginine (L-NMMA)-sensitive time-dependent fashion after Ad.CMV-iNOS. Other inducible genes that may be affected by NO and that may protect against potential oxidant-mediated LPS-induced apoptosis including 70-kDa heat shock protein, heme oxygenase-1, metallothionein, and Bcl-2 also were not elevated in an L-NMMA-sensitive, time-dependent fashion. Although the candidate gene product underlying NO-induced protection remains unclear, we did note that prolonged synthesis of NO inhibited LPS-induced activation of an interleukin-1beta-converting enzyme-like cysteine protease (cysteine protease protein-32-like) in a dithiothreitol-sensitive fashion, suggesting that S-nitrosylation of an important downstream target of convergence of apoptotic signals may contribute to the sensitivity of SPAECs to LPS.
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PMID:Nitric oxide inhibits lipopolysaccharide-induced apoptosis in pulmonary artery endothelial cells. 975 4

We have introduced the human bcl-2 gene under the control of the human metallothionein MTIIA promoter into the rat kangaroo PtK2 cell line. Two independent clones were obtained in which the levels of Bcl-2 protein expression can be controlled by the addition of metals in the culture medium. These cell lines were employed to investigate the effects of this protein in UV-induced apoptosis. Overexpression of Bcl-2 in PtK2 cells resulted in a delay in the appearance of apoptosis markers, such as chromatin condensation and internucleosomal DNA fragmentation. However, colony survival after UV was not affected, suggesting that Bcl-2 did not impose a definitive block for cell death. The elimination of cyclobutane pyrimidine dimers through photoreactivation 24 h after irradiation in cells overexpressing Bcl-2 did not affect apoptosis. This indicates that irreversible events in the signaling pathway of apoptosis occur in the period between irradiation and photoreactivation even in the presence of high levels of Bcl-2 protein can delay the onset of UV-induced apoptosis in these marsupial cells, early events triggered by the pyrimidine dimers, upstream from the Bcl-2 action, lead the cell to a state committed to die.
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PMID:Human Bcl-2 expression delays ultraviolet-induced apoptosis in marsupial cells. 982 1

Caspases and c-Jun N-terminal kinase (JNK) are activated in tumor cells during induction of apoptosis. We investigated the signaling cascade and function of these enzymes in cisplatin-induced apoptosis. Treatment of Jurkat T-cells with cisplatin induced cell death with DNA fragmentation and activation of caspase and JNK. Bcl-2 overexpression suppressed activation of both enzymes, whereas p35 and CrmA inhibited only the DEVDase (caspase-3-like) activity, indicating that the activation of these enzymes may be differentially regulated. Cisplatin induced apoptosis with the cytochrome c release and caspase-3 activation in both wild-type and caspase-8-deficient JB-6 cells, while the Fas antibody induced these apoptotic events only in wild-type cells. This indicates that caspase-8 activation is required for Fas-mediated apoptosis, but not cisplatin-induced cell death. On the other hand, cisplatin induced the JNK activation in both the wild-type and JB-6 cells, and the caspase-3 inhibitor Z-DEVD-fmk did not inhibit this activation. The JNK overexpression resulted in a higher JNK activity, AP-1 DNA binding activity, and metallothionein expression than the empty vector-transfected cells following cisplatin treatment. It also partially protected the cells from cisplatin-induced apoptosis by decreasing DEVDase activity. These data suggest that the cisplatin-induced apoptotic signal is initiated by the caspase-8-independent cytochrome c release, and the JNK activation protects cells from cisplatin-induced apoptosis via the metallothionein expression.
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PMID:Signaling and function of caspase and c-jun N-terminal kinase in cisplatin-induced apoptosis. 1201 40

Advances in molecular and cell biology have led to further understanding of the mechanisms of malignant growth and metastasis in human breast cancer cells. Initiation and progression of breast cancer results from mutations and the abnormal expression of many genes that control cellular proliferation, differentiation, invasion, metastasis and sensitivity to therapy (chemotherapy and radiation therapy). Inhibition of host immunity also plays a role in breast cancer progression. Many genes have been selected as targets for antisense therapy, including HER-2/neu, PKA, TGF-alpha, EGFR, TGF-beta, IGFIR, P12, MDM2, BRCA, Bcl-2, ER, VEGF, MDR, ferritin, transferrin receptor, IRE, C-fos, HSP27, C-myc, C-raf and metallothionein genes. The strategy behind antisense therapy is the development of specific therapeutic agents that aim to correct the mutations and abnormal expression of cellular genes in breast tumour cells by decreasing gene expression, inducing degradation of target mRNA and causing premature termination of transcription. Many in vitro and in vivo studies have investigated the therapeutic efficacy of oligonucleotides and antisense RNAs. These studies have demonstrated specific inhibition of tumour cell growth by antisense therapy and have shown synergistic inhibitory effects between antisense oligonucleotides or antisense RNA and conventional chemotherapeutic drugs used in the treatment of breast cancer. Antisense oligonucleotides have been modified to improve their ability to penetrate cells, bind to gene sequences and downregulate target gene function. Many delivery systems for antisense RNA and antisense oligonucleotides have been developed, including virus vectors (retrovirus, adenovirus and adeno-associate virus) and liposomes, to carry the antisense RNA or oligonucleotides through the cell membrane into the cytoplasm and nucleus of the tumour cells. However, in order to determine their feasibility antisense therapies need to be further investigated to determine their antitumour activity, pharmacokinetics and toxicity in breast cancer patients.
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PMID:Gene targets of antisense therapies in breast cancer. 1222 74

Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta, and in other subcortical nuclei associated with a widespread occurrence of Lewy bodies. The causes of cell death in Parkinson's disease are still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative stress have been proposed. We have examined 3-morpholinosydnonimine (SIN-1)-induced apoptosis in control and metallothionein-overexpressing dopaminergic neurons, with a primary objective to determine the neuroprotective potential of metallothionein against peroxynitrite-induced neurodegeneration in Parkinson's disease. SIN-1 induced lipid peroxidation and triggered plasma membrane blebbing. In addition, it caused DNA fragmentation, alpha-synuclein induction, and intramitochondrial accumulation of metal ions (copper, iron, zinc, and calcium), and enhanced the synthesis of 8-hydroxy-2-deoxyguanosine. Furthermore, it down-regulated the expression of Bcl-2 and poly(ADP-ribose) polymerase, but up-regulated the expression of caspase-3 and Bax in dopaminergic (SK-N-SH) neurons. SIN-1 induced apoptosis in aging mitochondrial genome knockout cells, alpha-synuclein-transfected cells, metallothionein double-knockout cells, and caspase-3-overexpressed dopaminergic neurons. SIN-1-induced changes were attenuated with selegiline or in metallothionein-transgenic striatal fetal stem cells. SIN-1-induced oxidation of dopamine to dihydroxyphenylacetaldehyde was attenuated in metallothionein-transgenic fetal stem cells and in cells transfected with a mitochondrial genome, and enhanced in aging mitochondrial genome knockout cells, in metallothionein double-knockout cells and caspase-3 gene-overexpressing dopaminergic neurons. Selegiline, melatonin, ubiquinone, and metallothionein suppressed SIN-1-induced down-regulation of a mitochondrial genome and up-regulation of caspase-3 as determined by reverse transcription-polymerase chain reaction. The synthesis of mitochondrial 8-hydroxy-2-deoxyguanosine and apoptosis-inducing factors were increased following exposure to 1-methyl-4-phenylpyridinium ion or rotenone. Pretreatment with selegiline or metallothionein suppressed 1-methyl-4-phenylpyridinium ion-, 6-hydroxydopamine-, and rotenone-induced increases in mitochondrial 8-hydroxy-2-deoxyguanosine accumulation. Transfection of aging mitochondrial genome knockout neurons with mitochondrial genome encoding complex-1 or melanin attenuated the SIN-1-induced increase in lipid peroxidation. SIN-1 induced the expression of alpha-synuclein, caspase-3, and 8-hydroxy-2-deoxyguanosine, and augmented protein nitration. These effects were attenuated by metallothionein gene overexpression. These studies provide evidence that nitric oxide synthase activation and peroxynitrite ion overproduction may be involved in the etiopathogenesis of Parkinson's disease, and that metallothionein gene induction may provide neuroprotection.
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PMID:Metallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons. 1288 Apr 80

Bcl-2, an inhibitor of apoptosis, is expressed in LPS-induced metaplastic goblet cells of rat airways. The present study investigated expression of Bcl-2 in airway mucous cells of persons with cystic fibrosis and tested in rats and mice whether its expression is responsible for sustaining metaplastic mucous cells. A significantly higher percentage of mucous cells expressed Bcl-2 in humans with cystic fibrosis compared with control subjects with no disease or subjects with other diseases. In LPS-instilled F344/N rats, the percentage of Bcl-2-positive mucous cells was decreased to background levels before the resolution of goblet cell metaplasia. Furthermore, intraperitoneal injection of rats with antisense oligonucleotides significantly reduced Bcl-2 expression and goblet cell metaplasia in nasal and pulmonary airway epithelia in rats. In contrast, sustained expression of Bcl-2 in transgenic mice by a metallothionein promoter caused increased LPS-induced goblet cell metaplasia over 8 days compared with wild-type mice. These studies demonstrate that Bcl-2 expression sustains goblet cell metaplasia in various species, that epithelial cell numbers are directly linked to the regulation of the numbers of goblet cells, and that downregulating Bcl-2 expression reduces goblet cell metaplasia.
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PMID:Bcl-2 sustains increased mucous and epithelial cell numbers in metaplastic airway epithelium. 1561 64

The molecular mechanism of sulforaphane on the induction of metallothionein (MT) genes in HepG2 cells and the antiproliferative effects of sulforaphane were investigated in this study. Treatment of the cells with sulforaphane at non-toxicity concentration (0-20 microM) resulted in coordinate increases in the induction of MT-I and MT-II mRNA, followed by corresponding increases in MT protein expression. Western blot analysis revealed the increased level of the transcription factor, Nrf2 in a time-dependent manner from sulforaphane-treated cells. Furthermore, sulforaphane activated the extracellular signal-regulated protein kinase (ERK), p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways. SB203580, a specific inhibitor of p38 and PD98059, a specific inhibitor of ERK, abolished sulforaphane-induced MT protein expression, whereas SP600125, a specific inhibitor of JNK, had no significant effect. At relatively high concentration (30-100 microM), sulforaphane is a cell growth modulator, as it induced apoptotic cell death characterized by internucleosomal DNA fragmentation and caused a rapid induction of caspase 3 activity, according to the appearance of the caspase 3 fragments and stimulated proteolytic cleavage of poly (ADP-ribose) polymerase in a time-dependent manner. Moreover, sulforaphane-induced apoptotic cell death was accompanied by upregulation of Bax and downregulation of Bcl-2 and Bcl-X(l) protein. Sulforaphane-induced DNA fragmentation was blocked by the N-acetyl-L-cysteine and catalase, suggesting that the death signaling was triggered by oxidative stress. Taken together these results strongly suggest that at low concentrations of sulforaphane, activation of MAPKs, such as ERK and p38 pathway, lead to Nrf2-mediated MT gene expression. Whereas at a higher concentration, sulforaphane is an effective apoptosis inducer in HepG(2) cells through regulation of Bcl-2 family molecular and activation of ICE/Ced-3 protease (caspase 3) cascade. The results from this study may provide more evidence for its chemopreventive function.
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PMID:Effect of sulforaphane on metallothionein expression and induction of apoptosis in human hepatoma HepG2 cells. 2431 95

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta and in other subcortical nuclei associated with a widespread occurrence of Lewy bodies. The causes of cell death in Parkinson's disease are still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative stress has been proposed. We have examined 3-morpholinosydnonimine (SIN-1)-induced apoptosis in control and metallothionein-overexpressing dopaminergic neurons, with a primary objective to determine the neuroprotective potential of metallothionein (MT) against peroxynitrite-induced neurodegeneration in PD. SIN-1 induced lipid peroxidation and triggered plasma membrane blebbing. In addition, it caused DNA fragmentation, alpha-synuclein induction, and intramitochondrial accumulation of metal ions (copper, iron, zinc, and calcium), and it enhanced the synthesis of 8-hydroxy-2-deoxyguanosine. Furthermore, it downregulated the expression of Bcl-2 and poly(adenosine diphosphate-ribose) polymerase, but upregulated the expression of caspase-3 and Bax in dopaminergic (SK-N-SH) neurons. SIN-1 induced apoptosis in aging mitochondrial genome knockout cells, alpha-synuclein-transfected cells, metallothionein double-knockout cells, and caspase-3-overexpressed dopaminergic neurons. SIN-1-induced changes were attenuated with selegiline or in metallothionein-transgenic striatal fetal stem cells. SIN-1-induced oxidation of dopamine (DA) to dihydroxyphenylacetaldehyde (DopaL) was attenuated in metallothionein-transgenic fetal stem cells and in cells transfected with a mitochondrial genome, and was enhanced in aging mitochondrial genome knockout cells, in metallothionein double-knockout cells, and caspase-3 gene-overexpressing dopaminergic neurons. Selegiline, melatonin, ubiquinone, and metallothionein suppressed SIN-1-induced downregulation of a mitochondrial genome and upregulation of caspase-3 as determined by reverse transcription polymerase chain reaction. These studies provide evidence that nitric oxide synthase activation and peroxynitrite ion overproduction may be involved in the etiopathogenesis of PD, and that metallothionein gene induction may provide neuroprotection.
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PMID:Peroxynitrite in the pathogenesis of Parkinson's disease and the neuroprotective role of metallothioneins. 1629 Dec 39

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