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)

Expression of the bcl-2 gene becomes deregulated in many non-Hodgkin lymphomas as the result of t(14;18) chromosomal translocations. Because bcl-2 regulates the survival of cells, and because its over-expression is associated with cellular resistance to killing by chemotherapeutic drugs and gamma-irradiation, this gene and its mRNA and protein products represent ideal targets for designing novel therapeutic strategies for the treatment of cancer. Here we describe the effects of an 18-mer phosphodiester oligonucleotide that is complementary to the first 6 codons of the bcl-2 mRNA's open reading frame. When tested for inhibition of in vitro protein synthesis using RNAse-H-supplemented reticulocyte lysates and RNA prepared by in vitro transcription of a human bcl-2 cDNA, the bcl-2 antisense (AS) oligomer completely abolished Bcl-2 protein production at 10 microM, but had no effect on the in vitro translation of a chicken bcl-2 RNA that contained three mismatches relative to the oligomer binding site on the human bcl-2 RNA. A control 18-mer having the same base composition as the AS oligomer but with scrambled order (SC) was not inhibitory. Addition of AS and SC oligomers to cultures of a NIH-3T3 fibroblast cell line that had been stably infected with a recombinant retrovirus containing the same human bcl-2 cDNA used for in vitro transcription/translation experiments revealed concentration-dependent reductions in the relative levels of the 26-kD human Bcl-2 protein (as determined by immunoblotting) by the AS but not by the SC oligomer. Similar results were obtained when AS and SC oligomers were applied to a t(14;18)-containing lymphoma cell line SU-DHL-4 that was cultured in low-serum media. When used at 200 microM, the bcl-2 AS oligomer produced 84-95% reductions in Bcl-2 protein levels in SU-DHL-4 cells but had relatively little effect on the levels of other mitochondrial control proteins, suggesting that the inhibitory effects were specific. Treatment of SU-DHL-4 cells with AS oligomer lead to essentially complete loss of bcl-2 mRNA from cells within 1 day of addition to cultures, but presumably because of the long half-life of the Bcl-2 protein (approximately 14 h), commensurate reductions in Bcl-2 protein levels did not occur until 3 days.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Investigations of antisense oligonucleotides targeted against bcl-2 RNAs. 840 Aug 1

Previous studies have shown that the bcl-2 gene encodes a mitochondrial protein that contributes to neoplastic cell expansion primarily by promoting cell survival through interference with "programmed cell death" (PCD), also termed "apoptosis." Because many chemotherapeutic drugs are capable of initiating pathways leading to apoptosis, we determined whether deregulated bcl-2 expression could render cells resistant to several drugs commonly used in the treatment of non-Hodgkin's lymphomas, including dexamethasone (DEX), methotrexate (MTX), 1-beta-D-arabinofuranosyl-cytosine (Ara-C), etoposide (VP-16), vincristine (VC), cisplatin (CP), and hydroperoxycyclophosphamide (4-HC). For these experiments, we achieved high levels of p26-Bcl-2 protein production in a human pre-B-cell leukemia line 697 by stable infection with a recombinant bcl-2-containing retrovirus and then compared these cells with control virus-infected 697 cells. Control 697 cells were induced to undergo apoptosis by all drugs tested as defined by DNA degradation into oligonucleosomal-length fragments, cell shrinkage, and subsequent cell death. In contrast, 697 cells with elevated Bcl-2 protein levels exhibited strikingly prolonged cell survival and markedly reduced DNA fragmentation when cultured in the presence of these antineoplastic agents. Although high levels of Bcl-2 protein protected 697 cells from the acute cytotoxic effects of DEX and the other drugs tested, Bcl-2 did not prevent these drugs from suppressing the proliferation of 697 cells. However, when 697 cells were treated with DEX or MTX for 3 days, then washed and cultured in semisolid media without drugs, bcl-2-virus-infected cells gave rise to colonies at much higher frequencies than 697 cells stably infected with control virus. These results indicate that by protecting 697 leukemic cells from the acute cytotoxicity of DEX and some other chemotherapeutic drugs, high levels of p26-Bcl-2 can create the opportunity for re-initiation of cell growth when drugs are withdrawn. The findings may be relevant to clinical correlative studies of non-Hodgkin's lymphoma patients that have found an association between worse prognosis and bcl-2 gene rearrangements or t[14;18] translocations.
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PMID:Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. 841 86

The t(14;18) chromosomal translocation occurs in most follicular non-Hodgkin's lymphomas and places the Bcl-2 gene on chromosome 18q21 into the immunoglobulin JH region on chromosome 14q32. This translocation can be exploited to detect clonal malignant cells bearing this genetic alteration. A polymerase chain reaction (PCR) assay amplifying over the major breakpoint region (mbr) and minor cluster region (mcr) was developed and optimized. In this report, the sensitivity and reproducibility of this semiquantitative assay, performed on a relatively large number of clinical samples is shown. A titration curve of DNA made from a t(14;18)- cell line admixed with increasing ratios of a t(14;18)+ cell line was used to demonstrate that one t(14;18)+ cell in 100,000 t(14;18)- cells could reproducibly be detected. Occult lymphoma cells, not detected by standard morphologic analysis, were demonstrated in almost two-thirds of the bone marrow and peripheral blood specimens obtained from untreated patients with follicular lymphoma. Of 11 bone marrow samples assessed, seven were positive for occult disease by PCR amplification over the mbr and one was positive over the mcr. Of these six positive marrow samples, only three had been reported positive by standard morphologic criteria. In addition, seven of nine peripheral blood samples assessed were positive over the mbr and one additional sample was positive over the mcr. None of these were morphologically positive. Seven of the above patients would have been upstaged if these results were utilized for staging, including two of three patients with stage I or stage II disease. PCR-detectable occult disease persisted in four of four patients assessed both pre- and post-treatment, even after aggressive multi-drug combination chemotherapy in two of these patients. The clinical significance of detecting this occult disease must await the study of larger numbers of patients and the clinical outcomes of patients with occult disease and patients without occult disease.
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PMID:Sensitive and reproducible detection of occult disease in patients with follicular lymphoma by PCR amplification of t(14;18) both pre- and post-treatment. 841 70

The most common translocation in human lymphoma, t(14;18)(q32;q21), recombines the bcl-2 gene with the immunoglobulin (Ig) heavy-chain locus leading to the production of high levels of chimeric RNAs and the resulting 26 kDa bcl-2 protein. The oncogenic role of the bcl-2 gene has been shown by the suppression of a variety of programmed cell deaths (apoptosis). Bcl-2 is able to interact with other members of the bcl-2 family through at least one of its conserved dimerization domains. Although overproduction of the wild-type protein appears sufficient for conferring a selective growth or a survival advantage to hematopoietic cells, the mode of activation of the proto-oncogene remains to be elucidated. In a first step, we examined and quantitated the expression of the bcl-2 gene in primary biopsies of non-Hodgkin's lymphomas (NHL) as well as in cell lines derived from NHLs. The results show that bcl-2 expression is found in a variety of hematopoietic lineages, but is most strongly associated with the B cell lineage. Within the B cell lineage, the expression levels vary depending on the differentiation as well as on the t(14;18) rearranged status. The quantitative measurements show high steady-state mRNA levels in early and in t(14;18) arranged B cells, whereas bcl-2 expression decreases with further B cell maturation and differentiation. In a second step we analyzed the bcl-2 mRNA for secondary genetic alterations, which may alter regulatory regions rendering it more tumorigenic. For this purpose, we chose a combined RT-PCR/SSCP method in order to screen out mutations of alleles which are not expressed. Different migration patterns of SSCP products were found only in two cell lines and subsequent sequencing revealed that the functional domains are not affected. Our data suggest that the dimerization properties of this protein are preserved in tumor cells and that modifications of the bcl-2 gene by the somatic hypermutation mechanism are not involved and do not influence the pathobiology of NHL.
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PMID:Preservation of functional and regulatory domains of expressed bcl-2 genes in non-Hodgkin's lymphoma. 855 21

The bcl-2 gene is rearranged in most cases of follicular lymphoma and the breakpoint clusters into two specific regions: mbr and mcr. Rearrangements to immunoglobulin heavy chain genes (IgH) result in a deregulation of the gene and increased transcription of mRNA for the bcl-2 protein. In chronic lymphocytic leukaemia (CLL) expression of bcl-2 protein is increased but rearrangement of the gene can be found only in a minority of cases: commonly a variant translocation with a breakpoint region located 5' of the bcl-2 gene (vcr) with preferential rearrangement to immunoglobulin light chain genes. We have analysed breakpoints in mbr and vcr in malignant cells from 96 patients with B-CLL, 45 with hairy cell leukaemia (HCL) and 41 with high- and low-grade non-Hodgkin's lymphomas (NHL). Vcr rearrangements were observed in nine patients (12%) with B-CLL. Four patients had co-migration of rearranged bcl-2 bands to kappa genes and two patients to IgH. Cytogenetic abnormalities involving 18q21, the site of the bcl-2 gene, was found in two cases only. In several cases with bcl-2 gene rearrangement chromosomal aberrations not including 18q21 were observed. In six patients (two B-CLL, one follicular lymphoma, one immunocytoma and two high-grade lymphomas), breakpoints in both vcr and mbr were found. In HCL a rearrangement in the vcr region was found in one case. Bcl-2 protein immunostaining of B-CLL showed intense bcl-2 expression in all cases and no correlation was found between gene rearrangement and protein expression. Our study confirms that breakpoints in the bcl-2 gene commonly cluster to the vcr region in B-CLL, but in most cases over-expression of bcl-2 protein has to be explained by other mechanisms than bcl-2 gene rearrangement. We also report that simultaneous breakpoints in mbr and vcr is a recurrent phenomenon in B-CLL and in other high- and low-grade non-Hodgkin's lymphomas.
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PMID:Bcl-2 rearrangements with breakpoints in both vcr and mbr in non-Hodgkin's lymphomas and chronic lymphocytic leukaemia. 861 30

The expression of a cell death-inducing gene, Bax, was investigated in 52 cases of Hodgkin's disease in parallel with Epstein-Barr virus and was compared with the immunodetection of other apoptosis-regulating proteins, Mcl-1, Bcl-2, and Bcl-x. Bax immunostaining was found in 92% of the cases, among them 28% with a strong signal in more than 75% of the Reed-Sternberg cells. Mcl-1 was positive in 80% of the cases, whereas Bcl-2 and Bcl-x were found in 53% and 88% of the cases, respectively. Of 48 (89%) Bax-positive tumors, 43 were found to express apoptosis-inhibiting proteins such as Mcl-1 or Bcl-2. With the exception of 1 case, all Bax-positive tumors also expressed either Bcl-2, Bcl-x, Mcl-1, or combinations of these anti-apoptotic proteins. No correlation was found between Bax expression and the presence of apoptotic cells as detected by morphology and the in situ 3' OH-DNA end-labeling technique. Our findings show that the apoptosis-inducing gene Bax expression is frequently expressed in Hodgkin's disease, providing a potential explanation for the good chemoresponses generally obtained for patients with this neoplastic disorder.
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PMID:Frequent expression of the cell death-inducing gene Bax in Reed-Sternberg cells of Hodgkin's disease. 863 Apr 13

The expression of the apoptosis-regulating genes Bcl-2, Bcl-x, Bax, Mcl-1, and p53 analyzed in 4 cases of human immunodeficiency virus (HIV)-associated Hodgkin's disease, in 36 cases of HIV-related non-Hodgkin's lymphomas (NHLs), and in 109 cases of non-HIV-related NHLs by using immunohistochemistry. HIV-associated Hodgkin's disease samples were positive for all markers. For the HIV-related NHL samples, 36, 66, 88, 100, and 94% of the cases were Bcl-2, Bcl-x, Bax, Mcl-1, and p53 were found to be expressed in 69, 65, 82, 83, and 42%, respectively. No significant differences were observed in Bax and Mcl-1 staining between HIV-unrelated NHLs of B cell and T cell types. In contrast, Bcl-2 was positive in 66/79 (83%) and 10/30 (33%) of B cell and T cell HIV-unrelated NHLs, respectively (P2 < 0.001). Peculiar patterns were observed for hairy cell leukemia (Bax+, Bcl-2+, Mcl-1-) and for anaplastic large cell lymphoma (Bax+, Mcl-1+, Bcl-2-) in HIV-unrelated NHLs. Of interest, all cases with a positive expression of Bax were also found to express either Mcl-1 and/or Bcl-2, suggesting that Mcl-1 and Bcl-2 may counteract the pro-apoptosis function of Bax in vivo by protein-protein interaction within the tumor cell, as demonstrated previously in vitro. These results suggest that apoptosis regulation may have a role in the pathogenesis of some HIV-related and HIV-unrelated NHLs.
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PMID:Immunodetection of apoptosis-regulating proteins in lymphomas from patients with and without human immunodeficiency virus infection. 868 41

CD95 (APO-1/Fas) is a member of the superfamily that includes the nerve growth factor and tumor necrosis factor receptors, OX40, CD27, CD30, and CD40. Present on a minority of resting blood lymphocytes, CD95 expression is upregulated on activated T and B lymphocytes and natural killer cells, where binding of the antigen by anti-Fas and anti-APO-1 antibodies has been shown to induce apoptosis. This CD95-mediated apoptosis is at least partially inhibited by expression of the Bcl-2 protooncogene. To evaluate possible roles of CD95 and Bcl-2 in growth regulation of lymphoid neoplasms, we studied by immunohistochemistry the expression of CD95 and Bcl-2 in 67 B- and 5 T-cell lymphomas, and 10 cases of Hodgkin's disease. In all, 29 B and 2 T cell lymphomas, and 9 cases of Hodgkin's disease expressed CD95. Compared with diffuse large B-cell and Burkitt-like lymphomas, lowgrade B-cell lymphomas more frequently expressed CD95 (52% versus 26%; P < .005). None of the B-cell small lymphocytic lymphomas or mantle cell lymphomas expressed CD95, whereas the majority of follicle center lymphomas, extranodal marginal zone B-cell lymphomas, and immunocytomas were CD95+. Of the 29 CD95+ B-cell lymphomas, only 33% of the high-grade group coexpressed Bcl-2, compared with 87% of the low-grade group (P < .04). Two of three peripheral T-cell lymphomas--including one anaplastic large cell lymphoma--expressed CD95. Staining for CD95 was seen in 9 of 10 cases of Hodgkin's disease. The infrequent expression of CD95 in high-grade B-cell lymphomas suggests an association between loss of CD95 expression/function and a more aggressive tumor grade. Whereas frequent coexpression of Bcl-2 with CD95 may protect low-grade B-cell lymphomas against CD95-mediated apoptosis, in the high-grade group such coexpression is infrequent, and other regulators besides Bcl-2 may be involved in modulating the apoptosis signal delivered by CD95.
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PMID:Expression of CD95 antigen and Bcl-2 protein in non-Hodgkin's lymphomas and Hodgkin's disease. 877 39

Recent work demonstrated that B7 expression by tumor cells can enhance antitumor immune responses. However, the B7 molecule is expressed abundantly on most non-Hodgkin's B-cell lymphomas and solid lymphoid tumors. How these tumor cells escape from immune surveillance mechanisms remains unclear. Lately, it has become clear that bcl-2 oncogene is overexpressed in a wide variety of human cancers and renders tumor cells more resistant to cytolytic T-cells (CTL) mediated cytotoxicity. We cloned B7 and B7/Bcl-2 transfectants and compared their susceptibilities to a human natural killer (NK) cell line and normal NK cells. The results demonstrate that Bcl-2 oncoprotein in tumor cells blocks B7-induced cytolysis mediated by a NK cell line and NK cells. Thus, they suggest that Bcl-2 oncoprotein plays a role in tumor avoidance of effective antitumor cytotoxicity.
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PMID:BCL-2 inhibits B7-induced MHC-unrestricted cytolysis mediated by a human NK cell line. 880 52

In vivo measurement of human somatic mutations may be a valuable biodosimeter of exposure to carcinogens and of cancer risk. We have surveyed translocations at the bcl2 locus in B lymphocytes, and mutations at hprt in T lymphocytes, in 120 individuals with varying exposure to radon and cigarette smoke. bcl2 t(14:18) translocation is the commonest chromosomal alteration observed in non-Hodgkins lymphoma (NHL). We observed a significantly larger range of bcl2 translocation frequency (range: 0-372 x 10(-6), median: 1.9 x 10(-6)) than of hprt mutation frequency (range: 0-76.4 x 10(-6), median: 11.1 x 10(-6)), which is likely the result of clonal proliferation of deathless B cell mutants. We observed that the frequencies of these two distinct lymphocytic mutations are significantly correlated. Although some of the correlated variation is explained by age, a significant correlation of bcl2 mutagenesis persists after age adjustment. Correlated mutagenesis at distinct loci in distinct cell types could be explained by the existence of a mutator phenotype or by variation in exposure to environmental mutagens. NHL is commoner in men than in women, and our data indicate a trend toward higher bcl2 mutagenesis in males than females. There is mounting epidemiological evidence for a worldwide increase in NHL, which may have an environmental basis; molecular epidemiological analysis of bcl2 mutagenesis in exposed populations might be especially relevant to the identification of putative environmental causes. Given the relative ease of the bcl2 assay versus the hprt assay, and the consistency with which data are reproduced from laboratory to laboratory, it is likely that the bcl2 assay will be soon added to the array of assays used in human mutational surveillance.
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PMID:Correlated mutagenesis of bcl2 and hprt loci in blood lymphocytes. 902 Mar 5


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