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)

During the last decades, major medical advances have been made in the understanding of cancer biology and led to the appearance of new diagnostic tools and development of innovative therapeutics. Some basic concepts in molecular medicine, oncogenes and tumour-suppressor genes are reviewed. Special topics are devoted to Ras, erbB2, p 53 and characteristical gene rearrangements, such as bcr-abl, RARA-PML, VDJ, bcl2-IgH. The greater knowledge of the molecular etiology of cancer will contribute to disease screening, diagnosis, staging and therapy, detection of residual or recurrent disease, and development of new treatments, such as gene therapy or drugs targeted to oncogene products.
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PMID:[Contribution of molecular and genetic biology in oncology]. 762 61

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the c-abl protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210BCR-ABL and p190BCR-ABL, are produced that are characteristic of chronic myelogenous leukemia and acute lymphoblastic leukemia, respectively. Their role in the etiology of human leukemia remains to be defined. Transformed murine hematopoietic cells can be used as a model of BCR-ABL function since these cells can be made growth factor independent and tumorigenic by the action of the BCR-ABL oncogene. We show that the BCR-ABL oncogenes prevent apoptotic death in these cells by inducing a Bcl-2 expression pathway. Furthermore, BCR-ABL-expressing cells revert to factor dependence and nontumorigenicity after Bcl-2 expression is suppressed. These results help to explain the ability of BCR-ABL oncogenes to synergize with c-myc in cell transformation.
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PMID:Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. 777 99

Oligodeoxynucleotides have been proposed as both in vitro and in vivo inhibitors of gene expression because of the specificity of Watson-Crick base pair hybridization. Phosphodiester oligodeoxynucleotides (normal DNA) cannot be used as drugs because they are nuclease sensitive. Significant efforts have been made to study phosphorothioate oligodeoxynucleotides, which have a sulfur atom substituted for one of the phosphate oxygen atoms at a nonbridging position. These oligodeoxynucleotides are nuclease resistant, and over the past year they have entered clinical trials. They have also been extensively examined in vitro and have been targeted to the bcr-abl and bcl2 messenger RNAs among others. Methods to maximize the intracellular oligodeoxynucleotide concentration have also been devised. However, significant problems remain, including the significant nonsequence specificity of phosphodiester oligodeoxynucleotides as well as questions of oligodeoxynucleotide uptake into and compartmentalization within cells. An improvement of our understanding of these phenomena is critical to the elaboration of this technology into a clinical therapeutic modality.
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PMID:Antisense oligodeoxynucleotides. 782 70

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

BCR-ABL is a chimaeric oncogene generated by translocation of sequences from the c-ABL protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210(BCR-ABL) and p190(BCR-ABL), are produced that are characteristic of chronic myelogenous leukemia and acute lymphoblastic leukemia, respectively. Their role in the aetiology of human leukemia remains to be defined. We have previously shown that the tumorigenic effect of BCR-ABL oncogenes is mediated by Bcl-2. In addition to Bcl-2, is a protein essential for transformation by BCR-ABL. However, it is not known how Bcl-2 and Ras fit together in cell transformation by BCR-ABL. The data presented here establish that Bcl-2 is a downstream target gene of the Ras signalling pathway in cells transformed by BCR-ABL, and that constitutive Ras activation results in constitutive expression of the gene. Conversely, a truncated form of the BCR-ABL, which lacks a critical BCR region required for activation of the Ras signalling pathway, failed to induce Bcl-2 expression. These results indicate that BCR-ABL prevents apoptosis by inducing Bcl-2 through a signalling pathway involving Ras and links constitutive Ras activation and Bcl-2 gene regulation. Hence, these results further imply that Ras is involved in both mitogenic signals and survival signals.
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PMID:Regulation of Bcl-2 gene expression by BCR-ABL is mediated by Ras. 909 20

The hallmark of chronic myeloid leukemia (CML) is the chimeric tyrosine kinase oncogene bcr-abl. Since expression of bcr-abl mRNA frequently increases with disease progression and a duplication of the Philadelphia chromosome (harbouring the bcr-abl hybrid locus) represents the most frequent karyotypic abnormality in acute phase CML, we hypothesized that the level of BCR-ABL protein may affect the disease phenotype. Therefore, the biological effects of high and low levels of BCR-ABL expression were compared in growth factor-dependent and -independent myeloid and lymphoid cell lines. Our results demonstrated that low levels of BCR - ABL were sufficient to render these cell lines growth factor independent and tumorigenic, but higher levels were mandatory for additional protection against apoptotic stimuli. The provision of growth factor or an activated ras oncogene did not afford the same degree of protection as high levels of BCR-ABL and there were qualitative differences between the survival signals mediated by BCR-ABL and Bcl-2. These results have enabled us to establish a dose-dependent hierarchy of BCR-ABL induced biological effects, thus distinguishing the activation of pathways mediating protection from cytokine withdrawal from those protecting against other apoptotic stimuli.
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PMID:BCR-ABL activates pathways mediating cytokine independence and protection against apoptosis in murine hematopoietic cells in a dose-dependent manner. 946 59

Bcr-Abl expression in leukemic cells is known to exert a potent effect against apoptosis due to antileukemic drugs, but its mechanism has not been elucidated. Recent reports have indicated that a variety of apoptotic stimuli cause the preapoptotic mitochondrial release of cytochrome c (cyt c) into cytosol, which mediates the cleavage and activity of caspase-3 involved in the execution of apoptosis. Whether Bcr-Abl exerts its antiapoptotic effect upstream to the cleavage and activation of caspase-3 or acts downstream by blocking the ensuing degradation of substrates resulting in apoptosis, has been the focus of the present studies. In these, we used (1) the human acute myelogenous leukemia (AML) HL-60 cells that are stably transfected with the bcr-abl gene (HL-60/Bcr-Abl) and express p185 Bcr-Abl; and (2) the chronic myelogenous leukemia (CML)-blast crisis K562 cells, which have endogenous expression of p210 Bcr-Abl. Exposure of the control AML HL-60 cells to high-dose Ara-C (HIDAC), etoposide, or sphingoid bases (including C2 ceramide, sphingosine, or sphinganine) caused the accumulation of cyt c in the cytosol, loss of mitochondrial membrane potential (MMP), and increase in the reactive oxygen species (ROS). These preapoptotic events were associated with the cleavage and activity of caspase-3, resulting in the degradation of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) and DNA fragmentation factor (DFF), internucleosomal DNA fragmentation, and morphologic features of apoptosis. In contrast, in HL-60/Bcr-Abl and K562 cells, these apoptotic stimuli failed to cause the cytosolic accumulation of cyt c and other associated mitochondrial perturbations, as well as the failure to induce the activation of caspase-3 and apoptosis. While the control HL-60 cells showed high levels of Bcl-2 and barely detectable Bcl-xL, HL-60/Bcr-Abl cells expressed high levels of Bcl-xL and undetectable levels of Bcl-2, a pattern of expression similar to the one in K562 cells. Bax and caspase-3 expressions were not significantly different between HL-60/Bcr-Abl or K562 versus HL-60 cells. These findings indicate that Bcr-Abl expression blocks apoptosis due to diverse apoptotic stimuli upstream by preventing the cytosolic accumulation of cyt c and other preapoptotic mitochondrial perturbations, thereby inhibiting the activation of caspase-3 and execution of apoptosis.
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PMID:Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3. 947 36

Bcr - Abl is the molecule responsible for both the transformation phenotype and the resistance to chemotherapeutic drugs found in chronic myelogenous leukemia (CML) cells. Wild-type HL-60, a transformed pro-myelocytic cell line, is very susceptible to apoptosis-inducing agents. We show here that expression of Bcr - Abl in HL-60 cells rendered them extremely resistant to apoptosis induced by a wide variety of agents. The anti-apoptotic effect of Bcr - Abl was found to be independent of the phase of the cell cycle. Treatment with antisense oligonucleotides directed to bcr decreased the expression of the ectopic bcr - abl and restored susceptibility to apoptosis. Double mutations affecting the autophosphorylation site and the phosphotyrosine-binding motif (FLVRES) have been previously shown to impair the transforming activity of Bcr - Abl in fibroblasts and hematopoietic cells, however HL-60 cells expressing this double mutant molecule exhibited the same level of resistance to apoptosis as those expressing the wild-type Bcr - Abl. Interestingly, wild type and mutant Bcr - Abl induced in HL-60 cells a dramatic down regulation of Bcl-2 and increased the levels of Bcl-xL. The level of Bax did not change in response to the presence of Bcr - Abl. Antisense oligonucleotides targeted to bcl-x downregulated the expression of Bcl-x, and increased the susceptibility of HL-60. Bcr - Abl cells to staurosporine. Importantly, HL-60 cells overexpressing Bcl-xL showed higher expression of Bcl-xL but lower resistance to apoptosis when compared to HL-60. Bcr - Abl cells. The results described here show that Bcr - Abl is a powerful mammalian anti-apoptotic molecule and can act independently of Bcl-2. Bcl-xL, however, seems to participate in part in Bcr - Abl-mediated resistance to apoptosis in HL-60 cells.
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PMID:Bcl-2-independent Bcr-Abl-mediated resistance to apoptosis: protection is correlated with up regulation of Bcl-xL. 952 37

Apoptosis is a genetically regulated cell death process which results in a variety of morphological changes like chromatin condensation and DNA fragmentation. The decision between survival or death in response to an apoptotic stimulus is determined and regulated in part by oncoproteins which include proteins of the Bcl-2 family (bcl-2, bax, bcl-xL) and bcr-abl. We investigated the effect of these proteins on the induction of this phenomenon in human promyelocytic leukemic HL60 cells and two multidrug resistant homologues selected respectively with vincristine (HL60/VCR) and daunorubicin (HL60R/DNR). We show that sensitive cells at 1 micron and HL60/VCR cells at DNR IC50 were able to undergo apoptosis while HL60R/DNR did not even at much higher concentration of DNR. However, treatment with synthetic C2-ceramide did not sensitize HL60/DNR cells to apoptosis. Cell death through apoptosis or necrosis was accompanied by acidification of the cytosol without mitochondrial membrane depolarization. Western blotting analysis shows that bax is expressed at slightly elevated level in HL60S/VCR in comparison with the other cells lines. Bcl-2 is overexpressed in HL60/VCR but not in HL60R/DNR. However, this cell line displayed a higher expression of bcl-xL. Interestingly, bcr-abl, a dysregulated tyrosine kinase was detected only in HL60R/DNR cells. DNR at the IC50, has no effect on expression of the oncoproteins. These data suggest that in addition of the multidrug resistance phenotype, bcr-abl translocation and bcl-xL overexpression could also account for the development of resistance to cell death induced by anthracyclines in leukemic cells.
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PMID:Two distinct modes of oncoprotein expression during apoptosis resistance in vincristine and daunorubicin multidrug-resistant HL60 cells. 1050 Aug 12

The effects of HIV-1 Tat protein on mitochondria membrane permeability and apoptosis were analysed in lymphoid cells. In this report we show that stable-transfected HIV-Tat cells are primed to undergo apoptosis upon serum withdrawal. This effect was observed in both the Jhan T cell line and the K562 cells, the latter expressing the bcr-abl chimeric gene, which confers resistance to apoptosis induced by different stimuli. Using a cytofluorimetric approach we have determined that serum withdrawal induces a disruption of the transmembrane mitochondrial potential (Deltapsim) followed by an increase of reactive oxygen species (ROS) and the subsequent DNA nuclear loss in K562-Tat cells but not in the K562-pcDNA cell line. These pre-apoptotic events were associated with the cleavage of the caspase-3, while the expression of Bcl-2, Bcl-XL and Bax proteins was not affected by the presence of Tat. Regardless of the steady state of the Bax protein, we found that in both K562 and K562-Tat cells, this protein is located in the nucleus, but after serum withdrawal its localization was mainly in the cytoplasm. The activity of caspase-3 detected in K562-Tat cells after serum withdrawal paralleled with the mitochondria permeability transition. Nevertheless, in Jhan-Tat cells the inhibition of this caspase with the specific inhibitor, z-DEVD-cmk, did not affect the disruption of the mitochondria potential induced by serum withdrawal. Interestingly, we found that HIV-Tat protein accumulates at the mitochondria in the K562-Tat cells cultured under low serum conditions, and this mitochondrial localization correlated with the Deltapsim disruption detected in these cells. In addition, HIV-1 Tat protein synergies with protoporphyrin IX (PPIX), a ligand of the mitochondrial benzodiazepine receptor, in the induction of apoptosis in both Jhan and K562 cells. Thus, HIV-1 Tat protein may induce apoptosis by a mechanism that involves mitochondrial PT and may contribute to the lymphocyte depletion seen in AIDS patients.
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PMID:Susceptibility of HIV-1-TAT transfected cells to undergo apoptosis. Biochemical mechanisms. 1060 13


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