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)

Mercuric chloride (HgCl2) as well as several drugs can induce T cell activation leading to systemic immune-mediated diseases in genetically susceptible individuals or rodents. T cell hybridomas represent a well-characterized model system for in vivo mechanisms of various stimuli-induced cell death. The cellular response to HgCl2 was examined using various T cell lines and particularly the murine T cell hybridoma 2B4.11. Exposure to HgCl2 induced both necrosis and apoptosis in a dose- and time-dependent way as demonstrated by DNA fragmentation analysis, flow cytometry of the whole cells and of isolated nuclei, and morphological examination. HgCl2-induced cell death was partly inhibited by cycloheximide. The expression of human Bcl-2 in 2B4.11 cells after transfection significantly prevented HgCl2-induced cell death but did not affect the susceptibility to apoptosis induced by an anti-CD3 epsilon mAb. Subcytotoxic doses of HgCl2 enhanced metabolic activity of Bcl-2 transfectants in contrast with mock-transfected cell line. Thus, we conclude that apoptosis is part of the cell death process induced by HgCl2 and that the ability of Bcl-2 to prevent the death of one particular cell line is stimulus-dependent suggesting the existence of different pathways leading to cell death.
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PMID:Mercuric chloride-induced programmed cell death of a murine T cell hybridoma. I. Effect of the proto-oncogene Bcl-2. 786 88

The mechanism by which the bcl-2 oncogene exerts its anti-apoptotic and antioxidant action is unknown. We found that expression of bcl-2 in superoxide dismutase-deficient (SOD-) Escherichia coli resulted in increased transcription of the KatG catalase-peroxidase, a 13-fold increase in KatG activity and a 100-fold increase in resistance to hydrogen peroxide. In addition, mutation rate was increased 3-fold, and katG and oxyR, a transcriptional regulator of katG induction, were required for aerobic survival. These data indicate that Bcl-2 acts as a pro-oxidant in E. coli, i.e. Bcl-2 generates reactive oxygen intermediates. In support of a pro-oxidant mechanism in eukaryotic cells, we found a 73% increase in superoxide dismutase activity in a murine B-cell line overexpressing Bcl-2. Increases in reduced glutathione and in oxyradical damage to DNA, previously observed in other overexpressing cell lines, are additional evidence for a pro-oxidant mechanism. Thus, Bcl-2 does not appear to be an antioxidant. Instead, Bcl-2 appears to influence levels of reactive oxygen intermediates that induce endogenous cellular antioxidants. This activity of Bcl-2 may control entry into apoptosis.
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PMID:The Bcl-2 oncoprotein functions as a pro-oxidant. 787 80

LMP-1, an Epstein-Barr virus membrane protein expressed during latent infection, has oncogenic properties, as judged from its ability to transform B lymphocytes and rodent fibroblasts. LMP-1 induces the expression of bcl2, an oncogene which protects cells from apoptosis, as well as of genes encoding other proteins involved in cell regulation and growth control. The mechanisms by which LMP-1 upregulates these proteins is unknown, but it is plausible that LMP-1 modifies signal transduction pathways that result in the activation of one or more transcription factors that ultimately regulate transcription of oncogenic genes. NF-kappa B, a transcription factor controlling the expression of genes involved in cell activation and growth control, has been shown to be activated by LMP-1. The mechanism(s) regulating this activation remains unknown. Our data indicate that increased NF-kappa B DNA binding and functional activity are present in B-lymphoid cells stably or transiently expressing LMP-1. I kappa B alpha is selectively modified in LMP-1-expressing B cells. A phosphorylated form of I kappa B alpha and increased protein turnover-degradation correlate with increased NF-kappa B nuclear translocation. This results in increased transcription of NF-kappa B-dependent-genes, including those encoding p105 and I kappa B alpha (MAD3). These results indicate that LMP-1 activates NF-kappa B in B-cell lines by targeting I kappa B alpha. Identification of the pathways activated by LMP-1 to result in posttranslational modifications of I kappa B alpha will aid in determining the role of this virus-host cell protein interaction in Epstein-Barr virus-mediated oncogenesis.
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PMID:LMP-1 activates NF-kappa B by targeting the inhibitory molecule I kappa B alpha. 788 65

The v-Rel oncoprotein of the avian Rev-T retrovirus malignantly transforms chicken spleen cells in vivo and in vitro. We previously described two temperature-sensitive (ts) mutants of v-Rel (v-G37E and v-R273H) that show a ts ability to transform chicken spleen cells and to bind to DNA in vitro. We now show that spleen cell lines transformed by ts v-Rel proteins at the permissive temperature undergo apoptosis when cells are shifted to the nonpermissive temperature. The levels of most proteins (including v-Rel, p53, c-Myc, Rb and Bcl-2) do not change in these cells even at advanced stages of apoptosis. However, the chicken I kappa B-alpha protein (also called p40), which is in a complex with v-Rel in transformed cells, is degraded when ts v-Rel-transformed cells are shifted to the nonpermissive temperature. In v-R273H-transformed cells, p40 is degraded without the appearance of proteolytic intermediates. In contrast, in v-G37E-transformed cells, p40 is cleaved to an intermediate species that is missing approximately 3-4 kDa from its amino terminus. This truncated form of p40 is found in a detergent-insoluble fraction and can also be detected in wild-type v-Rel-transformed cells that are induced to undergo apoptosis by treatment with cycloheximide. Both ts v-Rel proteins are ts for interaction with p40 in vitro. The results reported here indicate that v-Rel blocks a normal pathway of programmed cell death and that I kappa B-alpha can undergo multiple degradative pathways, which can be induced by alterations in the structure of the Rel protein to which it is bound.
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PMID:The v-Rel oncoprotein blocks apoptosis and proteolysis of I kappa B-alpha in transformed chicken spleen cells. 789 28

With the recent advances in molecular technology, diagnostic procedures of the diseases at a DNA level have been introduced in hematological fields. The diagnostic methods used are Southern blotting to detect gene rearrangements, Northern blotting to find gene expressions, RT-PCR (reverse transcriptase-polymerase chain reaction) to identify transcribed fusion messages, and PCR-SSCR (single strand conformation polymorphism) to detect mutated genes. Rearrangements within major Bcr (breakpoint cluster region) were observed in almost all cases in chronic myelogenous leukemia, and breakpoint were found within minor Bcr in Philadelphia-positive leukemia. The rearrangements within the second intron of the retinoic acid receptor-alpha and sixth intron (bcr 1), third intron (bcr 3) and sixth exon (bcr 2) of the PML gene were detected in all cases with acute promyelocytic leukemia. In malignant lymphoma, the rearrangements of immunoglobulin and T-cell receptor genes, and new genes such as Bcl-1, Bcl-2, Bcl-5, Tal-1, and Tal-2 were also reported and rearrangements of the Bcl-5 gene were found in this study using Bcl-5 specific probe which we have cloned. Point mutations and deletions of the genes involved in the coagulation and fibrinolysis system have been reported. One base insertion resulting in elongation of carboxy terminal region and one amino acid deletion in alpha 2-plasmin inhibitor gene were found in two cases of its deficiency. Further study revealed that mutated proteins were retained in the endoplasmic reticulum in the cells. With the development of the PCR method, identification of gene mutation is gradually carried out as a routine work.
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PMID:[Molecular study of hematological diseases]. 791 42

A technique for extracting DNA from archival and fresh tissue from fine needle biopsy (FNB) samples for the polymerase chain reaction (PCR) is described. The method was used to detect the bcl-2 oncogene in various cytologic lymphoid preparations. The DNA was amplified with primers specific for the major break point region of the t(14;18) translocation, and the presence of the bcl-2 oncogene was correlated with clinical, cytomorphologic, histologic and immunologic findings. Thirty patients who had FNB of lymphoid tissue were randomly selected, 18 retrospectively and 12 prospectively. Bcl-2 was present in 3 of 8 cases of reactive lymphadenopathy and 9 of 22 cases of non-Hodgkin's lymphoma. Of these, seven had follicular small cleaved cell lymphoma, and two had large cell lymphoma. Smears, both archival and fresh, and cell suspensions provided sufficient DNA for PCR amplification. The technique has potential applications in several areas of cytologic and hematologic practice.
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PMID:Use of archival and fresh cytologic material for the polymerase chain reaction. Detection of the bcl-2 oncogene in lymphoid tissue obtained by fine needle biopsy. 791 45

The roles of p53 as an inducer and Bcl-2 as an inhibitor of apoptotic death were explored in lymphoid cells. Lymphocytes from p53-/- mice were radioresistant, but unexpectedly, cycling T lymphoma cells and mitogenically activated T lymphocytes from these animals underwent apoptosis after irradiation or genotoxic drug treatment. Hence, p53 is not the only mediator of apoptosis provoked by DNA damage. Irradiated p53-/- lymphoblasts expressing Bcl-2 were subject to growth arrest but resisted apoptosis. Their accumulation in G1 as well as G2 is suggestive of a p53-independent DNA-damage G1 checkpoint. Since Bcl-2 increased the clonogenic survival of the irradiated cells, expression of survival genes may pose a greater impediment to genotoxic cancer therapy than loss of p53.
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PMID:DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. 795 87

Amebic destruction of neutrophils and macrophages is contact-dependent. Adherence is mediated by a galactose-specific surface lectin on the amebic membrane. The pathway by which contact-dependent cytolysis of the target cell occurs is unknown. We hypothesized that target cell death is due to the triggering of apoptosis (programmed cell death) by the amebae. The purpose of this study was to determine whether target cell DNA is fragmented into a ladder pattern characteristic of apoptosis and to test whether overexpression of Bcl-2, a protein that confers resistance to apoptotic death from some stimuli, blocks target cell killing. The murine myeloid cell line FDC-P1 transfected with a retrovirus construct expressing the Bcl-2 protein was shown to be resistant to the apoptotic death that the parental line undergoes upon growth factor deprivation. 51Cr-labeled FDC-P1 control or bcl-2-transfected cells were incubated with Entamoeba histolytica (4:1 cell/ameba ratio) and killing of the cells was assessed by 51Cr release. Both cell lines were susceptible to contact-dependent killing. Death induced by the amebae in the bcl-2-transfected cells resulted in a DNA ladder fragmentation pattern (using [125I]iododeoxyuridine-labeled target cell DNA) identical to that seen in the control cells undergoing apoptosis upon growth factor withdrawal. Target cell DNA fragmentation was inhibited by blocking adherence with galactose. Our data suggest that target cell killing by E. histolytica can occur via Bcl-2-independent apoptotic mechanism.
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PMID:Entamoeba histolytica: target cells killed by trophozoites undergo DNA fragmentation which is not blocked by Bcl-2. 795 63

Etoposide (VP-16) is one of several DNA-damaging agents that induce subcellular structural changes associated with apoptosis. VP-16 exerts its DNA-damaging and cytotoxic effects subsequent to interference with DNA topoisomerase II activity. VP-16 also stimulates c-jun and c-fos mRNA expression in some cell lines, including human leukemia K562 and HL-60 cells. To compare the temporal relationship between drug-induced c-jun expression and apoptosis, we examined cell morphology, cell viability, DNA integrity, and c-jun induction during VP-16 treatment of K562 and HL-60 cells. VP-16 (10 microM)-induced internucleosomal DNA damage and nuclear fragmentation were readily apparent within 6 hr in HL-60 cells but were absent in K562 cells treated for up to 24 hr. Some internucleosomal DNA damage was observed in K562 cells but only after treatment with 100 microM VP-16 for 24 hr. In contrast, VP-16-induced DNA single-strand breaks, VP-16-induced topoisomerase II/DNA covalent complex formation, and VP-16-mediated growth inhibition were similar in K562 and HL-60 cells. Also, the time course of VP-16-induced c-jun mRNA expression was comparable for both K562 and HL-60 cell lines. Western blot analysis of whole-cell lysates showed that Bcl-2 protein levels were 13-fold greater in HL-60 cells than in K562 cells. Thus, the resistance of VP-16-treated K562 cells to apoptosis was not attributable to protection by Bcl-2. Furthermore, the relatively high levels of Bcl-2 in HL-60 cells were not sufficient to protect these cells against apoptosis. Together, our results indicate that the temporal coupling of VP-16-induced DNA damage, c-jun expression, and apoptosis is cell type specific and suggest that different signaling pathways for apoptosis are operating in these two human leukemia cell lines.
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PMID:Differential induction of etoposide-mediated apoptosis in human leukemia HL-60 and K562 cells. 796 39

DNA-damaging agents such as ionizing radiation (IR) activate the tumor suppressor p53 and in some cases can cause apoptosis. M1 cells, which do not express the endogenous tumor suppressor gene p53, undergo apoptosis following activation of a temperature sensitive p53 transgene, where it has been shown that bax, an important mediator of apoptosis, is a p53 target gene (Selvakumaran et al, Oncogene 9, 1791-8, 1994). Since p53 can function as a transcription factor after activation by IR, the genetic response to this stress was examined in a panel of human cells with defined p53 status. Like the p53-regulated gene gadd45, bax was rapidly induced, as measured by increased mRNA levels, in the p53 wt (wild type) human myeloid line ML-1, and it was not induced in cells lacking functional p53. However, unlike other p53-regulated genes, bax was only induced in p53 wt cells in which IR also triggered apoptosis. In the case of bcl2, which opposes bax function, mRNA levels were reduced in ML-1 cells after IR. Thus, bax appears to be an unique p53-regulated gene in that its induction by IR not only requires functional p53 but also requires that the cells be apoptosis "proficient."
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PMID:Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. 797 Jul 35


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