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 occurrence of bcl-1 and bcl-2 gene rearrangements was investigated in 37 cases of high-grade B-cell lymphomas. Bcl-2 rearrangement was detectable only in single cases of primary centroblastic lymphoma with a follicular growth pattern, whereas secondary centroblastic lymphomas evolving from a centroblastic-centrocytic lymphoma were positive in up to 60 per cent of the cases analysed. Bcl-1 rearrangement was found only in one case of immunoblastic B-cell lymphoma with a history of pre-existing lymphoplasmacytoid immunocytoma. It is concluded that there may be a subgroup of centroblastic lymphomas with a biology similar to that of centroblastic-centrocytic lymphomas. The detection of bcl-1 rearrangement in high-grade lymphomas may indicate a secondary high-grade lymphoma.
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PMID:Gene rearrangement of bcl-1 and bcl-2 is confined to distinct subgroups of high-grade malignant B-cell lymphomas. 849 22

The Bcl-2 protein coded by the proto-oncogene bcl-2 is expressed in a variety of embryonic and postnatal tissues and is overproduced in several types of tumours. Bcl-2 expression suppresses apoptosis induced by a multitude of stimuli in diverse cell types without exerting significant effects on cell proliferation, and is believed to contribute to oncogenesis by extending cell survival. In certain B-cell lymphomas, chromosomal translocations result in a gain of function of Bcl-2 by overexpression. Here, we report that a deletion of a nonconserved region of human Bcl-2 (residues 51-85) confers a novel gain of function that not only suppresses apoptosis induced by the tumor suppressor protein p53 and the Myc oncoprotein but also permits continued cell proliferation. Our result raises the possibility that mutations within the bcl-2 gene may contribute to oncogenesis by both suppressing apoptosis and facilitating cell proliferation.
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PMID:Deletion of a nonconserved region of Bcl-2 confers a novel gain of function: suppression of apoptosis with concomitant cell proliferation. 865 86

The bcl-2 gene, originally identified in B-cell lymphomas, encodes for proteins which may assume oncogenic functions by blocking apoptosis. Bcl-2 proteins are broadly distributed among various tissues, including epithelial ones. Within the skin, bcl-2 is strongly expressed in melanocytes, but its further distribution is yet unclear. The Merkel cells, neuroendocrine-epithelial cells of the skin, are present within the epidermis and hair follicles, mostly nerve-associated, and are believed to be postmitotic and long lived. Possibly they give rise to the malignant Merkel cell carcinomas. In the present study we investigated the bcl-2 expression on the protein level by means of immunohistochemical techniques including double confocal laser scanning microscopy, as well as on the RNA level by RT-PCR techniques, in Merkel cells, Merkel cell carcinomas, and cell lines. Merkel cells were identified by double staining for cytokeratins 20 or 8/18. We demonstrate that fetal epidermal and dermal Merkel cells are immunostained for bcl-2 protein, most of them clearly weaker than melanocytes. Adult Merkel cells also express bcl-2 protein very heterogeneously, mostly weak. In contrast, Merkel cell carcinomas are usually strongly positive for bcl-2 protein with some degree of heterogeneity. This is different from malignant melanomas in which bcl-2 expression is reduced as compared to normal melanocytes. Bcl-2 gene expression was also shown for Merkel cell carcinoma cell lines on both the mRNA and the protein level. Possibly bcl-2 protein expression is downregulated during the life span of Merkel cells, arguing that they may succumb to a certain cell turnover. The comparably high bcl-2 protein level in Merkel cell carcinomas may reflect peculiar biological and clinical characteristics.
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PMID:Differences of bcl-2 protein expression between Merkel cells and Merkel cell carcinomas. 872 44

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

The Bcl-2 protein blocks a distal step in an evolutionarily conserved pathway for programmed cell death and apoptosis. The gene encoding this protein was first discovered because of its involvement in the t(14;18) chromosomal translocations commonly found in B-cell lymphomas, where it contributes to neoplastic cell expansion by preventing cell turnover due to programmed cell death. Overexpression of BCL-2 also occurs in many other types of human tumors, including cancers of the prostate, colon, and lung, and has been associated with chemoresistance and radioresistance in some types of malignancy. Conversely, expression of BCL-2 is frequently reduced in the circulating lymphocytes of persons infected with Human Immunodeficiency Virus (HIV), which are prone to apoptotic cell death. Since the discovery of Bcl-2 a decade ago, several other cellular and viral genes encoding homologous proteins have been identified, some of which suppress cell death akin to Bcl-2 (Bcl-XL, Mcl-1, A1/Bfl-1, Nr13, Ced-9, BHRF-1) and others which promote apoptosis (Bax, Bcl-Xs, Bak, Bik, Bad). Several of these Bcl-2 family proteins are capable of physically interacting with each other through a complex network of homo- and heterodimers. The expression of some of these other BCL-2 family genes becomes altered in human cancers, as well as in the setting of ischemia and some other pathological conditions, suggesting a potentially important role for these Bcl-2 homologs in human diseases characterized by either insufficient or excessive cell death. Despite intensive investigation, the mechanisms by which Bcl-2 and its homologs control cell life and death largely remain enigmatic. Knowledge about the specific domains in Bcl-2 family proteins that are required for interactions with other proteins and for function however is beginning to provide insights into the molecular mechanisms through which these proteins regulate the programmed cell death pathway in normalcy and disease.
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PMID:Mechanisms of Bcl-2 family protein function and dysfunction in health and disease. 895 Apr 68

The aim of this study was to investigate the changes involved in the evolution of nine cases of recurrent B-cell lymphomas. Using the polymerase chain reaction (PCR) on formalin-fixed, paraffin-embedded tissue from both the primary and the recurrent lymphoma of each case, monoclonality was demonstrated in every tumour. In all nine cases, the recurrent lymphoma was shown to belong to the same clone as the primary lymphoma. Eight of these cases were then investigated by immunohistochemistry for changes in Bcl-2 and p53 expression. Five out of eight of the primary lymphomas showed Bcl-2 overexpression. Two of the three cases initially negative for Bcl-2 expression became positive in the recurrence. One out of eight of the primary lymphomas was positive for p53 expression. Of the seven negative cases, one became positive for p53 expression in the recurrence. Both of the p53-positive cases showed high-grade histology. This study shows that Bcl-2 overexpression is probably an important early event in the development of B-cell lymphomas, although it may occur as a post-neoplastic event. p53 mutation is probably more important as a late event and may be associated with high-grade transformation.
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PMID:Changes in Bcl-2 and p53 expression in recurrent B-cell lymphomas. 895

Bcl-2 suppresses drug-induced apoptosis in vitro, although in many cases, this results only in a delayed onset of cell death. In vivo survival signals from the extracellular environment may also contribute to drug resistance and may act with Bcl-2 to promote long-term cell survival. Ligation of CD40 on B-lymphocytes in germinal centers (GCs) can suppress apoptosis induced by calcium ionophore or anti-IgM in vitro. We asked whether a combination of Bcl-2 expression and the provision of a culture environment that mimicked that of the GC [CD40 ligation and interleukin 4 (IL-4)] could increase the ability of B lymphoma cells to resist drug-induced apoptosis. A Burkitt lymphoma (BL) cell line transfected with either human bcl-2 (BL-bcl-2) or control plasmid (BL-Sv2) was used to examine the effects of Bcl-2 overexpression on the cellular response and long-term survival after treatment with the DNA-alkylating drug chlorambucil (CMB) in the presence or absence of CD40 ligation and IL-4. Administration of 20 microM CMB completely prevented cell proliferation. This was associated with an increase in p53 protein levels within 24 h, without an elevation in p21, Bax, or Mdm2 proteins. Analyses of cell cycle distribution and of cyclin B expression demonstrated that both cell lines arrested at G2/M, where they died. Fifty % of BL-Sv2 cells died within 2 days, whereas 50% cell death was not observed in the BL-bcl-2 cultures until 6 days had passed. Cross-linking of CD40 with a monoclonal antibody elevated Bcl-xL protein levels by 3 h and also provided a delay in CMB-induced death. Ninety-six h after the addition of 20 microM CMB, 78% of the BL-Sv2 cells were apoptotic, whereas ligation of CD40 on BL-Sv2 cells reduced the proportion of apoptotic cells to 38%. Overexpression of Bcl-2 (in BL-bcl-2 cells) reduced apoptosis to 41%. However, when the BL-bcl-2 cells were treated with CMB together with ligation of CD40, apoptosis was reduced further to only 17% at 96 h. The Bcl-2-mediated delay in the execution of CMB-induced apoptosis did not translate significantly to increased clonogenicity. In contrast, the provision of BL-Sv2 cells with an ability to interact with the adhesion molecule vascular cell adhesion molecule-1, CD40 ligation, and IL-4 significantly increased clonogenic survival, and this was improved in BL-bcl-2 cells exposed to these GC-derived signals. These data demonstrate that the kinetics of drug-induced apoptosis can be modulated by Bcl-2 as well as by IL-4, vascular cell adhesion molecule-1, and CD40 ligation, the latter possibly involving the function of Bcl-xL. That these factors appear to act together to enhance proliferative potential after DNA damage has important implications regarding the development of drug resistance in B-cell lymphomas and future strategies for improved chemotherapy.
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PMID:Germinal center-derived signals act with Bcl-2 to decrease apoptosis and increase clonogenicity of drug-treated human B lymphoma cells. 915 89

Bcl-6 (LAZ-3) and Bcl-2 gene rearrangements have been respectively reported in 20-35 per cent and 10-25 per cent of diffuse large B-cell lymphomas (DLBCLs). Although these genetic lesions have been associated with different clinical outcomes (i.e., more favourable in Bcl-6 rearranged cases and poorer in Bcl-2 rearranged cases), their prognostic significance is still controversial. In the present study, we have investigated by Southern blot analysis the Bcl-6 and Bcl-2 gene configuration in a series of 80 lymph nodes involved by well-characterized DLBCLs, histologically defined according to the REAL and the updated Kiel classifications. The molecular findings have been correlated with the clinical features at presentation and with response to therapy. The majority of cases (57/80 = 71.2 per cent) had a centroblastic morphology. Bcl-6 rearrangements were detected in 23/80 cases (28.8 per cent), and were similarly associated with centroblastic (18/57 = 31.6 per cent) or immunoblastic (3/11 = 27.3 per cent) histotypes. In contrast, Bcl-2 was found to be rearranged in only three cases of centroblastic lymphoma (3.8 per cent). No significant differences were found between Bcl-6 rearranged and germline cases, as far as the clinical features at presentation are concerned. Forty-one patients, in whom the lymph node biopsy was performed at diagnosis, could be evaluated for response to treatment and clinical outcome. Most of these cases (30/41 = 73.2 per cent) were nodal DLBCL, without extranodal site involvement. Analysis of the clinical outcome showed no statistically significant differences between Bcl-6 rearranged and Bcl-6 germline cases (actuarial overall survival 50 per cent vs. 48 per cent, event-free survival 45 per cent vs. 46 per cent, at 4 years). These findings confirm that Bcl-6 rearrangements are the most frequent genetic lesion in DLBCL. The incidence of Bcl-2 involvement in our series is significantly lower than the figures reported in other studies, mainly from North American countries, probably reflecting heterogeneous patient selection and/or epidemiological variability. Finally, our results suggest that no relevant clinical differences are observed between Bcl-6 rearranged and Bcl-6 germline cases, when nodal DLBCLs are considered.
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PMID:Pathogenetic and clinical implications of Bcl-6 and Bcl-2 gene configuration in nodal diffuse large B-cell lymphomas. 942 82

The bcl-2 proto-oncogene encodes an inner mitochondrial membrane protein that blocks apoptosis and programmed cell death in human lymphoid tissue. In this study a monospecific anti-human bcl-2 antibody that is reactive in formalin-fixed tissues was used with an avidin-biotin complex immunoperoxidase method to evaluate 41 cases of lymphoproliferative disorders of the salivary gland. The study cases were 26 primary salivary gland lymphomas (including 21 B-cell lymphomas four T-cell lymphomas and one true histiocytic lymphoma) and 15 cases of myoepithelial sialadenitis. Bcl-2 expression is restricted to the mantle zone and interfollicular lymphocytes around reactive germinal centers of myoepithelial sialadenitis. Seventeen of the 21 B-cell lymphomas were positive for bcl-2, and were composed of mucosa-associated lymphoid tissue (MALT), centrocytic, centroblastic-centrocytic and centroblastic lymphomas. Noticeably, all 11 cases of MALT lymphoma were bcl-2 positive. In contrast, staining for bcl-2 was present in only one of four cases of T-cell lymphomas and was negative in one true histiocytic lymphoma. The expression of bcl-2 protein was also investigated in the ductal systems and epimyoepithelial islands of salivary glands from patients with malignant lymphoma and myoepithelial sialadenitis. While salivary ducts in eight of 15 cases of myoepithelial sialadenitis immunostained for bcl-2, epimyoepithelial islands showed bcl-2 expression in only five cases of myoepithelial sialadenitis. We found that ductal cells in the salivary gland from patients with primary non-Hodgkin's lymphomas expressed bcl-2 protein. It was of interest that epimyoepithelial islands in all cases of MALT lymphoma displayed bcl-2 expression whereas other subtypes of B-cell lymphoma, T-cell lymphoma and true histiocytic lymphoma were invariably negative. These results indicate that bcl-2 is expressed in a wide variety of non-Hodgkin's lymphomas, especially when all 11 cases of MALT lymphoma are bcl-2 positive. Epimyoepithelial islands in MALT lymphoma express this oncoprotein, and their ability to induce bcl-2 synthesis resulted in the prevention of apoptosis and prolonged cell survival. Furthermore, the expression of bcl-2 protein in the lymphoma cells may be responsible for the induction of bcl-2 expression in the adjacent epimyoepithelial islands through a lymphocyte chemical mediator.
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PMID:Detection of the apoptosis-suppressing oncoprotein bcl-2 in salivary gland lymphoma. 958 34


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