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)

The majority of non-Hodgkin's B-cell lymphomas contain a t(14;18) translocation that places the bc12 gene into juxtaposition with the transcriptically active Ig heavy-chain locus, thus deregulating the expression of this proto-oncogene. The bc12 gene product is a membrane-associated mitochondrial protein that regulates cell survival through unknown mechanisms. Although overproduction of the normal protein appears sufficient for conferring a selective growth or survival advantage to B cells, point mutations that alter the coding region of translocated bc12 genes have been described previously by others in a lymphoma cell line. However, it is not known whether somatic mutations that alter BCL2 proteins occur in vivo or whether they result from chemotherapy or arise through other mechanisms. For these reasons, we obtained DNA from the t(14;18)-containing tumors of five patients who had not undergone treatment for their disease, and used a polymerase chain reaction (PCR)-mismatch technique for rapid identification of point mutations in a portion of the bc12 open reading frame (ORF) corresponding to the first 131 aminoacids (aa) of the 239 aa p26 BCL2 protein. DNAs from two t(14;18)-containing cell lines were also analyzed. Point mutations in this region of the bc12 gene ORF were detected in three of five patients' tumors and in both cell lines. PCR-mismatch analysis of bc12 in cell lines and non-Hodgkin's lymphoma cases that lacked the t(14;18) translocation was negative, thus establishing the specificity of these results. DNA sequencing determined that these mutations are predicted to produce aa substitutions in the BCL2 proteins of two of the primary tumors and one of the cell lines. Interestingly, two of the patients contained an identical C----T transition that resulted in a nonconservative aa substitution (proline----serine) at position 59 of the BCL2 protein. Further analysis excluded the possibility that these mutations represented hereditary polymorphisms or PCR artifacts. A cluster of four point mutations within the translocation + bc12 allele of one patient had hallmarks of the somatic hypermutation mechanism that is associated with Ig genes and that contributes to antibody diversity. Because of the region of the bcl2 gene analyzed in these t(14;18) translocations is located nearly 300 kbp from the Ig heavy-chain locus, our data suggest that the Ig gene somatic hypermutation mechanism can act over extreme distances of DNA. It remains to be established whether these somatic mutations that alter BCL2 proteins influence the pathobiology of nonHodgkin's lymphomas.
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PMID:Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas. 133 99

The bcl-2 gene, which is overexpressed in human follicular B-cell lymphomas, has been found to extend cellular lifespan through inhibition of apoptosis, or programmed cell death. However, the physiological role of the Bcl-2 protein in lymphocyte development is unclear. We have established a transgenic mouse line that expresses high levels of the Bcl-2 protein in both cortical and medullary thymocytes, disrupting the normal pattern of expression of this gene. We found that in these mice, immature thymocytes became resistant to apoptosis mediated by corticosteroids and calcium ionophores. Untreated thymocytes also exhibited a survival advantage in suspension cultures compared with controls. In addition, overexpression of bcl-2 enabled a proportion of thymocytes and peripheral T cells to escape the process of clonal deletion, which normally eliminates self-reactive T cells during thymocyte maturation. These findings implicate the Bcl-2 protein in regulating the lifespan of maturing thymocytes and in the antigenic-selection process.
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PMID:Inhibition of thymocyte apoptosis and negative antigenic selection in bcl-2 transgenic mice. 149 93

The Bcl-2 proto-oncogene was discovered at the t(14;18) breakpoint found in most follicular B-cell lymphomas and some diffuse large-cell lymphomas. Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and extending cell survival by blocking programmed cell death. We examined Bcl-2 protein expression in 82 hematologic malignancies and reactive lymphoid processes. All lymphomas with Bcl-2 rearrangement demonstrated high levels of Bcl-2 protein. However, most follicular and diffuse lymphomas without Bcl-2 rearrangement also displayed intense Bcl-2 staining. In these cases, mechanisms other than classic translocation may be deregulation Bcl-2. The pattern of Bcl-2 staining in follicular lymphoma is the inverse of the pattern in reactive hyperplasia, confirming a role for Bcl-2 immunolocalization in routine diagnosis. Small lymphocytic malignancies, including small lymphocytic lymphoma, mantle zone lymphoma, and chronic lymphocytic leukemia, expressed intermediate levels of Bcl-2. Bcl-2 protein varied in plasma cell dyscrasias. Bcl-2 protein levels in T-cell lymphomas reflected their corresponding stage of development. No substantial Bcl-2 was present in the Reed-Sternberg cells of nodular sclerosing Hodgkin's disease. Chronic myelogenous leukemia was strongly positive for Bcl-2, consistent with the presence of Bcl-2 in normal myeloid progenitors. Immunohistochemistry identified an expanded spectrum of hematopoietic neoplasms in which Bcl-2 may provide a cell survival advantage.
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PMID:Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms. 186 40

High-grade B-cell lymphomas, whether originated in a lymph node or in mucosa-associated lymphoid tissue (MALT), show similar morphologic traits, a fact that has fueled a long-running controversy about whether they represent different entities. They differ, however, in that some high-grade MALT lymphomas show less aggressive clinical behavior, a focal low-grade component being identified in some of them. In a search for bcl-2 protein expression, we have found a significant difference between nodal (39/48) and MALT high-grade B-cell lymphoma (1/15) (P less than 0.01). Bcl-2 gene product is an inner mitochondrial membrane protein able to give a survival advantage to B-cell lines by blocking programmed cell death. This protein is usually expressed by memory or resting B cells, most activated B cells being bcl-2 negative, except in lymph-node-originated high-grade B-cell lymphomas, which appear to be mainly bcl-2 positive. Presence of bcl-2 protein in nodal large-cell lymphomas seems to be independent of a t(14;18) translocation, only being found in 19 to 28% of these lymphomas, although it constitutes a definite difference between both tumors, suggesting the existence of different molecular genetic characteristics and pathogenesis, and is possibly related to the more aggressive clinical behavior of nodal high-grade tumors.
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PMID:Different bcl-2 protein expression in high-grade B-cell lymphomas derived from lymph node or mucosa-associated lymphoid tissue. 195 37

The bcl-2 gene is consistently associated with t(14; 18) chromosomal translocations observed in a large fraction of human B-cell lymphomas. The t(14; 18) translocation results in deregulated expression of the bcl-2 gene and synthesis of inappropriately high levels of the Bcl-2 protein. Gene transfer studies suggest a role for Bcl-2 in cell survival, growth enhancement and oncogenic transformation. To test the suggestion that GTP-binding by Bcl-2 may mediate its biological effects we characterized the GTP-binding proteins in lymphoid cells expressing Bcl-2. Expression of several small GTP-binding proteins was found to be ubiquitous and did not vary with levels of Bcl-2. By using immunological, electrophoretic and cell-fractionation techniques, we separated Bcl-2 from G proteins of small relative molecular mass (Mr) and showed that it is incapable of binding GTP. Our results show that small Mr G proteins are widely expressed in lymphoid cells and that Bcl-2 is not a novel member of this GTP-binding protein family.
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PMID:Small G proteins are expressed ubiquitously in lymphoid cells and do not correspond to Bcl-2. 211 53

The distribution of Bcl-2 oncoprotein was studied immunohistochemically in formaldehyde-fixed and paraffin-embedded reactive and neoplastic lymphoid tissue. The potential of Bcl-2 for the differential diagnosis of follicular lesions was emphasized, and the results on follicular lesions were correlated with those of polymerase chain reaction (PCR) assay of the immunoglobulin heavy chain gene rearrangement. In hyperplastic lymphoid tissue, Bcl-2 reactivity was widespread, including germinal center surroundings, scattered cells within the germinal centers, and the T-cell areas in general. Distinctively negative lymphoid populations included the majority of germinal center cells, and the negative staining pattern was maintained in cases of florid hyperplasia. In contrast, follicular lymphoma cells were consistently Bcl-2 positive. The immunohistochemical Bcl-2 reactivity of lymphoma follicles correlated with the clonal PCR amplification pattern of the immunoglobulin heavy chain gene; all Bcl-2-negative hyperplasias revealed a non-clonal pattern. Clusters of monocytoid B cells were Bcl-2 negative, whereas monocytoid B-cell lymphomas and closely related MALT lymphomas were positive. All other small cell non-Hodgkin's lymphomas of B-cell types showed nearly uniform Bcl-2 reactivity, whereas large cell B-cell lymphomas were variably positive (74%). In Hodgkin's cells, Bcl-2 reactivity was seen in the neoplastic populations of most cases of nodular sclerosis and mixed cellularity types, whereas the L&H and Reed-Sternberg cells in lymphocyte predominance Hodgkin's disease were negative in most cases. Bcl-2 immunohistochemistry thus appears very valuable in the differential diagnosis of follicular hyperplasia and neoplasia, and it may help to distinguish between reactive and neoplastic monocytoid B cells. However, Bcl-2 immunohistochemistry is not useful in the subtyping of B-cell lymphomas.
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PMID:Bcl-2 oncoprotein is widespread in lymphoid tissue and lymphomas but its differential expression in benign versus malignant follicles and monocytoid B-cell proliferations is of diagnostic value. 748 87

We have investigated the precise distribution of human B-lymphocyte subpopulations (CD5+ B lymphocyte, Leu-8+ lymphocyte, immunoglobulin D (IgD)+ lymphocyte, alkaline phosphatase (ALPase)+ B lymphocyte and bcl-2 protein+ B lymphocyte) within the mantle zones (MZs) and phenotypic characterization of human CD5+ B lymphocytes using immunohistochemical techniques and flow cytometric analysis. IgD+ lymphocytes and ALPase B lymphocytes were confined to the inner layer and outer layer of the MZs of secondary follicles, respectively. CD5+ B lymphocytes and Leu-8+ B lymphocytes were mostly located in the inner layer of the MZs. Bcl-2 protein+ B lymphocytes were seen throughout the MZs. The precise distribution pattern of human B-lymphocyte subpopulations may help further understanding of the histogenesis and features of B-cell lymphomas, particularly mantle cell-derived lymphomas as well as the B-cell differentiation pathway. A minor population of CD5+ B lymphocytes expressed IgD. Almost all the CD5+ lymphocytes did not express ALPase. The data support the fact that CD5+ B lymphocytes are located more in the inner layer than in the outer layer of the MZs. Leu-8 and bcl-2 protein were detected in a large population of CD5+ B lymphocytes. In addition, Ki-67 antigen was not expressed on the CD5+ B lymphocytes. The data suggest that human CD5+ B lymphocytes may be long-living and resting (G0 and G1a stage) cells possessing the capability of continuously recirculating between blood and lymph nodes to participate in some immune responses. Moreover, Leu-8 and CD44 were detected in the majority of CD5+ B lymphocytes but intercellular adhesion molecule-1 (ICAM-1) and very late antigen-4 (VLA-4) were detected in the minority. The data may account for a high percentage of Leu-8 and CD44 expression and a low percentage of ICAM-1 and VLA-4 expression on B-chronic lymphocytic leukemia (B-CLL), which is considered to be a neoplastic counterpart of normal CD5+ B lymphocyte.
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PMID:Phenotypic characterization of human B-lymphocyte subpopulations, particularly human CD5+ B-lymphocyte subpopulation within the mantle zones of secondary follicles. 751 26

The bcl-2 gene was originally cloned because of its involvement in B-cell lymphomas and encodes a 25-kD integral membrane protein that has been shown to inhibit programmed cell death (also termed apoptosis) in a wide variety of circumstances. The Epstein-Barr Virus (EBV) also has been implicated in B-cell malignancies and interestingly contains an open reading frame (BHRF-1) predicting a 19-kD protein with 22% homology to Bcl-2. To compare the functions of p26-Bcl-2 and p19-BHRF-1, we stably introduced expression plasmids encoding these proteins into a murine interleukin-3 (IL-3)-dependent hemopoietic cell line, 32D. Removal of IL-3 from cultures of control-transfected 32D cells resulted in internucleosomal DNA cleavage (a hallmark of programmed cell death) and loss of cell survival. In contrast, 32D cells containing high levels of p26-Bcl-2 or p19-BHRF-2 proteins exhibited prolonged survival and markedly delayed DNA degradation under the same conditions of IL-3 deprivation. As a first attempt to determine the functional importance of amino acid sequences that are conserved between the Bcl-2 and BHRF-1 proteins, we used site-specific mutagenesis to replace two conserved cysteine residues with alanines (positions 158 and 219) in the human Bcl-2 protein. Comparisons of the wild-type and cysteine-minus human Bcl-2 proteins in S49 lymphoma cells revealed equivalent ability to block glucocorticoid-induced cell death and DNA fragmentation, indicating that these two conserved cysteines are not critical for Bcl-2 oncoprotein function. Investigations in 32D cells of an avian homolog of Bcl-2 cloned from the chicken also revealed conservation of function with the human Bcl-2 protein, despite the presence of a 48-amino-acid region of divergent sequence. Taken together, these data demonstrate that despite marked differences in their predicted amino-acid sequences, the human, chicken, and EBV versions of Bcl-2 have retained the structural characteristics necessary to interface with pathways involved in the regulation of programmed cell death in murine cells. The findings thus contribute to the mapping of functional domains in Bcl-2 proteins, and raise the possibility that the EBV-encoded p19-BHRF-1 protein may be able to substitute for p26-Bcl-2 in the development of some types of cancer.
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PMID:Evolutionary conservation of function among mammalian, avian, and viral homologs of the Bcl-2 oncoprotein. 777 49

The p53 gene located in the short arm of chromosome 17 at position 17p13, is involved in the negative regulation of cellular growth. p53 mutation seems to be the most frequent genetic alteration found in human cancer. Mutant conformation of the p53 gene is associated with cell proliferation and tumour progression, and in most cases implies p53 stabilization, which renders the p53 protein detectable through the use of immunohistochemical techniques. p53 expression is a frequent finding in high grade lymphomas of either B or T cell lineage, having been detected in 30% of cases in our series. The focal presence of p53+ cells was seen in a wide range of low and high grade lymphomas, including lymphadenitis and reactive tonsils. In 37.5% of cases this increased expression of p53 was secondary to mutation in highly conserved regions (exons 5-8). Unlike findings reported in other tumours, in lymphomas, p53 expression seems to be secondary to genetic alterations other than p53 mutation. Initial data suggest that the MDM2 protein could be involved in inactivating p53 protein in most of these cases. Finally, p53 expression has been found to be a poor prognostic marker in high grade B-cell lymphomas in a large series of cases. High p53 expression was associated with a short survival, this relation being stronger in cases with simultaneous bcl2 expression.
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PMID:p53 expression in non-Hodgkin's lymphomas: a marker of p53 inactivation? 777 62

Many non-Hodgkins B-cell lymphomas possess a deregulated bcl-2 gene resulting in a phenotype that is apparently resistant to programmed cell death (apoptosis). We have used a mouse lymphoma cell line (S49.1) that undergoes apoptosis in response to a variety of stimuli to determine the effect of bcl-2 expression on induction of apoptosis. S49 cells were stably transfected with recombinant amphotrophic retroviruses carrying either a G418 antibiotic resistance gene alone (S49-NEO) or this gene in combination with a bcl-2 complementary DNA (S49-Bcl-2). Three different agents previously shown to activate apoptosis by different pathways in S49 cells (dexamethasone, the calcium ionophore A23187, and cycloheximide) were used to examine the effect of bcl-2 expression on cell growth and apoptosis caused by multiple signal transduction pathways. Dexamethasone (DEX) treatment inhibited cell growth and stimulated cell death in S49-NEO cells. Although S49-Bcl-2 cells exhibited a similar antiproliferative response, they failed to die in response to steroid treatment. Western blot analysis revealed no difference in the levels of glucocorticoid receptor protein in the two cell lines, and both responded to glucocorticoid with a profound inhibition of protein synthesis. Cycloheximide (CX) and A23187 also had antiproliferative and cell killing effects in both cell types, although higher concentrations of each agent were needed to kill S49-Bcl-2 cells. To determine whether the loss of viability in response to these drugs was due to apoptosis, cells were examined morphologically and DNA integrity was examined by gel electrophoresis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bcl-2 inhibits glucocorticoid-induced apoptosis but only partially blocks calcium ionophore or cycloheximide-regulated apoptosis in S49 cells. 800 91


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