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

The Epstein-Barr virus (EBV) genome contains an open reading frame, BHRF1, that encodes a presumptive membrane protein with sequence similarity to the proto-oncogene bcl2, which is linked to human B-cell follicular lymphoma. Potential roles for BHRF1 in EBV's ability to growth transform human B cells and to replicate in B cells in culture were investigated by generating EBV mutants that lack most of the open reading frame. This was accomplished by recombination of plasmids carrying mutations in BHRF1 with the transformation-defective EBV strain P3HR1. Because BHRF1 resides close to the deletion in P3HR1 that renders this strain transformation defective, B-cell transformation could be used to select for recombination events in the region. B-cell clones were established by recombinants which lacked most of the BHRF1 open reading frame, although most of these initial B-cell transformants also carried nonrecombinant (BHRF1+) P3HR1 genomes, at levels ranging from a fraction of a copy to four copies per cell. Secondary B-cell transformants that lacked BHRF1+ EBV at detectable levels were found to release transforming, BHRF1-deficient EBV at levels that were within the normal range for EBV-immortalized B-cell clones. These studies demonstrate that BHRF1 is nonessential for growth transformation of B cells and for virus replication and release from these cells in culture.
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PMID:BHRF1 of Epstein-Barr virus, which is homologous to human proto-oncogene bcl2, is not essential for transformation of B cells or for virus replication in vitro. 131 10

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 number of lymphocytes in an animal is remarkably constant despite antigen-driven proliferation and a high rate of B-cell lymphopoiesis. This reflects the relatively brief lifespan of many newly generated B cells and argues for a well-regulated death mechanism. Even so, a secondary immune response can be generated years after a primary exposure to antigen. Antigen that might restimulate B cells persists for extended periods on follicular dendritic cells in the light zone of germinal centres. Antigen-binding B cells have also been found months after the end of obvious cell division. The precise signal that enables certain B cells to emerge as long-term surviving memory cells is unknown. Bcl-2, an inner mitochondrial membrane protein, blocks programmed cell death in B cells. We report here that this proto-oncogene maintains immune responsiveness. Transgenic mice overproducing Bcl-2 have a long-term persistence of immunoglobulin-secreting cells and an extended lifetime for memory B cells.
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PMID:Bcl-2 maintains B cell memory. 190 51

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

Follicular lymphoma, the most common human lymphoma, characteristically has a t(14; 18) interchromosomal translocation. It is typically an indolent disease comprised of small resting B cells, but frequently develops into a high-grade lymphoma. The t(14; 18) translocates the Bcl-2 gene, generating a deregulated Bcl-2-immunoglobulin fusion gene. Bcl-2 is a novel inner mitochondrial membrane protein that extends the survival of certain cells by blocking programmed cell death. To determine the oncogenic potential of the t(14; 18) translocation, we produced transgenic mice bearing a Bcl-2-immunoglobulin minigene that structurally mimicked the t(14; 18). An indolent follicular hyperplasia in these transgenic mice progressed to a malignant diffuse large-cell lymphoma. The long latency, progression from polyclonal to monoclonal disease, and histological conversion, are all suggestive of secondary changes. Half of the immunoblastic high-grade lymphomas had a rearranged c-myc gene. Our transgenic mice provide an animal model for tumour progression in t(14; 18) lymphoma and show that prolonged B-cell life increases tumour incidence.
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PMID:Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). 198 77

The t(14; 18) chromosomal translocation of human follicular B-cell lymphoma juxtaposes the bcl-2 gene with the immunoglobulin heavy chain locus. The bcl-2 immunoglobulin fusion gene is markedly deregulated resulting in inappropriately elevated levels of bcl-2 RNA and protein. Transgenic mice bearing a bcl-2 immunoglobulin minigene demonstrate a polyclonal expansion of resting yet responsive IgM-IgD B cells which display prolonged cell survival but no increase in cell cycling. Moreover, deregulated bcl-2 extends the survival of certain haematopoietic cell lines following growth-factor deprivation. By using immunolocalization studies we now demonstrate that Bcl-2 is an integral inner mitochondrial membrane protein of relative molecular mass 25,000 (25k). Overexpression of Bcl-2 blocks the apoptotic death of a pro-B-lymphocyte cell line. Thus, Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and interfering with programmed cell death independent of promoting cell division.
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PMID:Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. 225 Jul 5

We have identified a 24-kilodalton protein that is the product of the human bcl-2 gene, implicated as an oncogene because of its presence at the site of t(14;18) translocation breakpoints. The Bcl-2 protein was detected by specific, highly sensitive rabbit antibodies and was shown to be present in a number of human lymphoid cell lines and tissues, as well as in mouse B cells transfected with a bcl-2 cDNA construct. Characterization of the Bcl-2 protein demonstrated that it has a lipophilic nature and is associated with membrane structures, probably by means of its hydrophobic carboxy-terminal membrane-spanning domain. In t(14;18)-carrying cell lines, the protein is predominantly localized to the perinuclear endoplasmic reticulum, with a minor fraction in the plasma membrane. These properties, together with the observations that Bcl-2 does not have a characteristic signal peptide and is not glycosylated, suggest that it is an integral-membrane protein that spans the bilayer at its C-terminal hydrophobic region but is exposed only at the cytoplasmic surface. The relative abundance of the Bcl-2 protein in various human lymphoid cell lines correlated with transcription of the bcl-2 gene. The protein was abundant in all t(14;18)-carrying cell lines and lymphomas and was also found at lower levels in pre-B-cell lines and nonmalignant lymphoid tissues that do not carry t(14;18) translocations. These results suggest that the Bcl-2 protein is functional in normal B lymphocytes and that a quantitative difference in its expression may play a role in the pathogenesis of lymphomas carrying the t(14;18) translocation.
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PMID:The bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18) translocation. 265 3

Fas is a type I membrane protein and its activation by binding of the Fas ligand or an agonistic anti-Fas antibody induces apoptosis in Fas-bearing cells. In this report we prepared lysates from cells treated with anti-Fas antibody. The lysates induced apoptotic morphological changes in nuclei from normal mouse liver, accompanied by DNA degradation. The apoptosis-inducing activity was quickly generated in cells by anti-Fas antibody and was found in the soluble cytosolic fraction. Induction of the activity in cells was inhibited by a tetrapeptide, acetyl-Tyr-Val-Ala-Asp-chloromethylketone, a specific inhibitor of interleukin-1 beta converting enzyme. Addition of COS cell lysates containing Bcl-2 to the assay significantly inhibited the apoptotic process, indicating that the in vitro process reflected apoptosis that occurs in intact cells.
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PMID:Apoptosis by a cytosolic extract from Fas-activated cells. 748 9

An ability of the Epstein-Barr virus latent membrane protein LMP1 to enhance the survival of infected B cells through upregulation of the bcl-2 oncogene was first suggested by experiments involving gene transfection and the selection of stable LMP1+ clones (S. Henderson, M. Rowe, C. Gregory, F. Wang, E. Kieff, and A. Rickinson, Cell 65:1107-1115, 1991). However, it was not possible to ascertain whether Bcl-2 upregulation was a specific consequence of LMP1 expression or an artifact of the selection procedure whereby rare Bcl-2+ cells already present in the starting population might best be able to tolerate the potentially toxic effects of LMP1. We therefore reexamined this issue by using two different experimental approaches that allowed LMP1-induced effects to be monitored immediately following expression of the viral protein and in the absence of selective pressures; activation of the NF-kappa B transcription factor and upregulation of the cell adhesion molecule ICAM-1 were used as early indices of LMP1 function. In the first approach, stable clones of two B-cell lines carrying an LMP1 gene under the control of an inducible metallothionein promoter were induced to express LMP1 in all cells. Activation of NK-kappa B and upregulation of ICAM-1 occurred within 24 h and were followed at 48 to 72 h by upregulation of Bcl-2. In the second approach, we tested the generality of this phenomenon by transiently expressing LMP1 from a strong constitutively active promoter in a range of different cell types. All six B-cell lines tested showed NF-kappa B activation in response to LMP1 expression, and this was followed in five of six lines by expression of ICAM-1 and Bcl-2. In the same experiments, all three non-B-cell lines showed NF-kappa B activation and ICAM-1 upregulation but never any effect upon Bcl-2. We therefore conclude that Bcl-2 upregulation is part of the panoply of cellular changes induced by LMP1 but that the effect is cell type specific. Our data also suggest that whilst NF-kappa B may be an essential component of LMP1 signal transduction, other cell-specific factors may be required to effect some functions of the viral protein.
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PMID:Upregulation of bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell-specific response that is delayed relative to NF-kappa B activation and to induction of cell surface markers. 752 93

The CD40 ligand (CD40L) is an activation-induced surface membrane protein expressed by CD4+ T helper cells in lymphoid follicles, and is involved in the contact-dependent signaling-mediated activation, proliferation, and differentiation of CD40+ B cells. Using immunohistochemistry, the present study analyzes the cell microenvironment of lymphoid tissues in two cases of X-linked hyper-IgM syndrome, a congenital immunodeficiency caused by mutations of the CD40L gene, and which represents a unique model to dissect the functional and morphologic consequences of disrupted CD40/CD40L interactions. Prominent primary B follicles are identified in the lymph nodes and in the extranodal lymphoid tissues from both cases, but tiny collections of Bcl-2-, MIB1/Ki67+ centroblasts are also found in one case. Despite the CD40L defect, intrafollicular CD4+CD57+ T helper cells, identified by anti-parvalbumin mAb, are normally present. However, a severe depletion of follicular dendritic cells, recognized by Abs against NGFR, CD21 and CD23, and lack of expression of the Ag recognized by KiM4p on these cells, are noticed. Finally, no major alterations of the architecture and cellular composition of the paracortical T cell area are found. A large number of plasma cells exclusively expressing IgM were detected in the colon lamina propria in one of the patients, who also had extremely elevated IgM serum levels. Taken together, these data support the idea that ineffective CD40/CD40L interactions determine both abortive germinal center cell reaction as well as severe depletion and phenotypical abnormalities of follicular dendritic cells, thus impairing the functional development of B follicles. Recurrent or persisting antigenic stimulation in mucosal tissues is likely to play a major role in determining and maintaining elevated IgM serum levels.
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PMID:Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells. 753 26


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