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

The bcl-2 oncogene is activated as a consequence of the t(14;18) chromosomal translocation in human follicular lymphomas. Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis. The bcl-2 protein is associated with the inner mitochondrial membrane, however, the biochemical function of bcl-2 is unknown. Transgenic mice which overexpress bcl-2 provide evidence for bcl-2's role in memory B cells and thymic education as an intracellular survival factor. Additional regulators of apoptosis, such as the p53 tumor suppressor gene, may be altered in human cancers as one step in tumorigenesis.
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PMID:The bcl-2 oncogene and apoptosis. 128 68

Chromosomal translocation within B and T cell malignancies has proven a rich source for proto-oncogenes. The obligate DNA breaks within immunoglobulin (Ig) and T cell receptor (TCR) loci are frequently the sites of recurrent translocations. Burkitt's lymphoma established the paradigm by introducing the myc oncogene from chromosome segment 8q24 into the Ig heavy chain gene locus at 14q32. Molecular cloning of an aberrant Ig rearrangement in follicular lymphoma revealed Bcl-2. Bcl-2 constitutes the first member of a new category of oncogenes: regulators of programmed cell death. Bcl-2 blocks apoptosis and maintains long-term immune responsiveness including B-cell memory. The PRAD1 gene of parathyroid adenomas appears to be the elusive Bcl-1 gene of t(11;14)(q13;q32) bearing lymphomas. It proves to be a novel G1 cyclin. Acute lymphoblastic leukemias (ALL) pre-B phenotype produce a E2A/PBX fusion protein that possesses the leucine zipper of E2A with the homeodomain of PBX. Two molecular forms of the BCR/ABL fusion protein are produced by the Philadelphia chromosome. A deregulated p210 tyrosine kinase is found in chronic myelogenous leukemia, while a p190 form predominates in Ph+ ALL. In contrast, T-cell ALLs introduce a potpourri of genes into their T cell receptor loci. However, a common theme is emerging. These oncogenes (Ttg1, Ttg2, SCL, LylI, H0X11) all belong to classic families of transcription factors, possessing LIM domains, helix-loop-helix motifs, or homeodomains. Provocatively, these transcription factors are normally intended for lineages other than T cells. These genes have widened the horizons of both oncogenesis and normal development.
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PMID:Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. 159 Oct 3

Correlations between cytogenetics, histology, and clinical course continue to emerge in studies of non-Hodgkin's lymphomas. The previously recognized association between the t(14;18) chromosomal translocation and follicular lymphoma has been confirmed; abnormalities of chromosome 3 have correlated specifically with diffuse large cell lymphoma and abnormalities of chromosome 1 have been frequently present in T-cell lymphomas. Rearrangements involving 11q13 (bcl-1) occur most commonly in diffuse lymphocytic lymphoma of intermediate differentiation. Several new recurrent chromosomal abnormalities have also been described. The molecular fine structure of the t(8-14) chromosomal translocation in Burkitt's lymphoma appears to differ between endemic (Epstein-Barr virus-associated) and sporadic cases. In endemic Burkitt's lymphomas, the chromosomal breakpoint is usually far upstream of c-myc oncogene, leaving the regulatory region of the gene intact. In sporadic tumors, a large part of the regulatory region is separated from the gene and transcription is initiated at sites within the first intron. These data raise the possibility that Epstein-Barr virus may contribute to the deregulation of the c-myc gene and that this interaction may be required for tumorigenesis in the presence of some, but not all, types of c-myc damage arising from chromosomal translocations. Partner proteins that oligomerize with c-Myc have been identified in humans and mice (Max and Myn). The partners share with c-Myc the DNA-binding and coiled-coil motifs that are recognized in many other proteins and that function as transcriptional regulators. The Bcl-2 protein has been shown to be a mitochondrial inner membrane protein that blocks programmed cell death (apoptosis). Viral expression has been demonstrated in Epstein-Barr virus-associated Hodgkin's disease, and the spectrum of Epstein-Barr virus-associated lymphoproliferative disease has been expanded to include some T-cell malignancies. A new human herpesvirus has been associated with some cases of Hodgkin's disease.
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PMID:Biology of the lymphomas: cytogenetics, molecular biology, and virology. 166 Nov 67

The control of cell survival is of central importance in tissues with high cell turnover such as the lymphoid system, and its disruption may be a critical step in tumorigenesis. Genes homologous to bcl-2, the oncogene implicated in human follicular lymphoma, play a key role in regulating physiologic cell death (apoptosis). Bcl-2 and its relatives bcl-x and bax encode intracellular membrane-bound proteins that share homology in three domains with a wider family of viral and cellular proteins. The Bcl-2 and Bcl-x proteins enhance the survival of lymphocytes and other cell types but do not promote their proliferation. High levels of Bax or of a smaller Bcl-x variant antagonize the survival function of Bcl-2. The mechanism by which Bcl-2 promotes cell survival remains unknown, but it appears to require association with Bax. Bcl-2 may combat the action of cysteine proteases thought to trigger apoptosis. Bcl-2 is not essential for embryogenesis or lymphoid development. However, upregulation of Bcl-2 appears to be the normal mechanism for positive selection of developing lymphocytes, and its continued expression is critical for survival of mature peripheral B and T cells. Constitutive expression of Bcl-2 does not abrogate deletion of self-reactive lymphocytes, nor disturb T lymphoid homeostasis; however, it substantially increases the pool of mature noncycling B cells. The risk of B lymphoid tumors is also enhanced, probably because Bcl-2 can countermand the apoptotic action of other oncoproteins such as Myc. Expression in tumors of bcl-2 and other cell survival genes may constitute a major barrier to the success of genotoxic cancer therapy.
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PMID:Regulation of lymphocyte survival by the bcl-2 gene family. 761 33

t(14;18) is the most common translocation in human lymphoid malignancy and results in bcl-2 overexpression. Bcl-2 blocks apoptosis and constitutes the initial member of a new category of oncogenes, ie, regulators of cell death. Bcl-2-Ig transgenic mice develop follicular hyperplasia and progress to malignant B-cell lymphoma. To assess the oncogenic potential of bcl-2 in the T-cell lineage, a cohort of 68 lckpr-bcl-2 transgenic mice and 56 control littermates were monitored for signs of malignancy over a 24-month period. Eighteen (26%) lckpr-bcl-2 mice developed diffuse, predominantly large-cell lymphomas at a mean age of 18 months. In contrast, only one nontransgenic control mouse developed lymphoma. CD3 surface expression and clonal T-cell receptor beta rearrangements support the T-lineage classification of these neoplasms. lckpr-bcl-2-enforced lymphomas are predominantly CD4+CD8-, consistent with a mature peripheral T-cell phenotype. These data provide support for the thesis that violation of homeostasis through the repression of cell death can be a primary mechanism of tumorigenesis in multiple lineages.
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PMID:Peripheral T-cell lymphoma in lckpr-bcl-2 transgenic mice. 763 29

Bcl-2 protooncogene, originally discovered at the chromosomal breakpoint of the t(14;18) in follicular lymphoma, is known to regulate the process of programmed cell death or apoptosis. The inhibition of apoptosis is thought to be one of the mechanisms involved in the development of tumors. To investigate the possible association of bcl-2 protooncogene with the tumorigenesis of neuroblastomas, the authors examined bcl-2 expression by immunohistochemistry in 49 neuroblastomas and 7 ganglioneuromas. The distribution of apoptotic cells was also examined by the TUNEL method (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling). Bcl-2 oncoprotein was detected in the cytoplasm in 40 of 49 neuroblastomas (81.6%). There was no correlation between bcl-2 oncoprotein expression and the clinical features of neuroblastoma. The incidence of bcl-2-positive tumors in ganglioneuroma was significantly lower than that in neuroblastoma (28.6%) (P < .01). TUNEL stained the nuclei of tumor cells in 11 of 34 (32.4%) neuroblastomas. TUNEL-positive cells tended to be located around calcifications in neuroblastomas in patients less than 1 year old. Examination of serial sections showed that apoptotic cells were distributed in the area where bcl-2 oncoprotein was not expressed. What we have observed indicates that apoptosis of neuroblastoma cells may be regulated by bcl-2 expression. Our observations suggest that the survival of neuroblastoma cells might be promoted by bcl-2 expression and that bcl-2 might be associated with the tumorigenesis of neuroblastomas.
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PMID:Bcl-2 oncoprotein expression and apoptosis in neuroblastoma. 766 11

Irradiation of mammalian cells can cause cell cycle perturbations and apoptotic cell death. We have investigated the modulation of these physiologic end points by growth factor stimulation: irradiation of a murine hematopoietic cell line in the presence of interlekin-3 (IL-3) induces G1 arrest, and irradiation in the absence of IL-3 results in rapid apoptotic cell death. Both of these end points are dependent on p53. Transient removal of IL-3 at the time of irradiation results in decreased clonogenic survival of irradiated cells. The removal of IL-3 results in a failure of the irradiated cells to arrest at the G1 checkpoint, despite induction of p53 and p21WAF1/CIP1, and then the cells enter S-phase where they undergo apoptosis. There are no cytokine-related changes in Bcl-2, Bax, or Bcl-x protein levels that could account for the modulation of G1 arrest versus apoptosis by growth factors. In contrast, rapid p53-independent alterations of basal levels of gadd45 and p21WAF1/CIP1 expression are linked to IL-3 withdrawal, suggesting a potential mechanism for this modulation. Constitutive activation of cytokine-like pathways with induced expression of v-Src or activated c-Raf inhibits the radiation-induced apoptosis and the alterations in p21WAF1/CIP1 and gadd45 expression. These observations suggest additional molecular mechanisms that can contribute to the development of radioresistance and resistance to apoptosis during tumorigenesis and provide an explanation for the observed lack of p53 mutations in some tumor types. In addition, these data suggest that oncogenic changes occurring during multistep tumorigenesis could be classified as those that either enhance or decrease apoptosis tendencies.
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PMID:Growth factor modulation of p53-mediated growth arrest versus apoptosis. 769 49

Cells are eliminated in a variety of physiological settings by apoptosis, a genetically encoded process of cellular suicide. Apoptosis comprises an intrinsic cellular defence against tumorigenesis, which, when suppressed, may contribute to the development of malignancies. The bcl-2 oncogene, which is activated in follicular lymphomas, functions as a potent suppressor of apoptosis under diverse conditions. Here we describe the complementary DNA cloning and functional analysis of a new Bcl-2 homologue, Bak, which promotes cell death and counteracts the protection from apoptosis provided by Bcl-2. Moreover, enforced expression of Bak induces rapid and extensive apoptosis of serum-deprived fibroblasts. This raises the possibility that Bak is directly involved in activating the cell death machinery.
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PMID:Induction of apoptosis by the Bcl-2 homologue Bak. 771 30

Bcl-2 oncoprotein, a member of a new category of oncogenes associated with the regulation of programmed cell death (apoptosis), has been considered to be involved in biological processes such as tumorigenesis and tumor development. To determine the role of bcl-2 oncoprotein in lung cancer, we preliminarily examined the expression of this protein in various histological types. Immunohistochemical staining using monoclonal bcl-2 oncoprotein antibody was performed in surgically resected frozen specimens. Bcl-2 staining was seen in nine of 13 small cell lung cancers (69%), while only 18 out of 69 non-small cell lung cancers (26%) expressed bcl-2 oncoprotein, showing a significantly increased incidence of bcl-2 oncoprotein expression in the former histological type. Considering the greater aggressiveness of small cell lung cancer compared to non-small cell lung cancer, the possibility exists that the high prevalence of bcl-2 oncoprotein expression in small cell lung cancer is closely associated with tumorigenesis and tumor development.
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PMID:High prevalence of bcl-2 oncoprotein expression in small cell lung cancer. 776 30

We report overexpression of the proto-oncogene bcl-2 in gastrointestinal adenocarcinoma and its precursor lesions. The bcl-2 proto-oncogene is centrally involved in the oncogenesis of human follicular lymphoma via a chromosomal translocation t(14;18)(q32;q21) and is also expressed in the epithelial regenerative compartment or the basal crypts of the normal colon and small intestine. We describe an immunohistochemical analysis of fixed, paraffin-embedded tissue using both a polyclonal rabbit and a monoclonal mouse antibody to the Bcl-2 protein. In addition to confirming bcl-2 expression in normal colonic and small intestinal crypts, we also observed expression in the gastric epithelial regenerative compartment, the mucous neck region. No increased expression was found in nonneoplastic or inflammatory gastrointestinal conditions, including ulcerative colitis, Crohn's disease, or inflammatory or hamartomatous polyps. Increased bcl-2 expression, however, was present in hyperplastic colonic polyps and in the majority of dysplastic lesions, from the earliest precursors through large adenomas, high grade flat dysplasia, and adenocarcinoma, all in comparison with adjacent internal control normal epithelium. Increased expression was present in dysplastic glandular lesions from all gastrointestinal sites, including colon, small bowel, and stomach. Furthermore, bcl-2 expression was frequently abnormal in nondysplastic epithelium surrounding dysplastic lesions, suggesting that altered expression occurred before the development of morphological dysplasia. Specifically, directly contiguous morphologically nondysplastic epithelium often showed abnormal bcl-2 expression throughout the full length of the crypt-villus axis. This expression pattern gradually diminished to involve only the crypt base (the normal pattern of expression), proceeding away from malignant or dysplastic lesions. Abnormal bcl-2 immunoreactivity in 1), the earliest precursor dysplastic lesions and its persistence throughout neoplastic progression and 2), contiguous morphologically unaltered nondysplastic epithelium suggests that bcl-2 alterations occur early during the morphological and molecular sequence of events leading to gastrointestinal epithelial neoplasia.
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PMID:The bcl-2 proto-oncogene and the gastrointestinal epithelial tumor progression model. 785 28


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