Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Profound cellular immunodeficiency occurs as the result of mutations in proteins involved in both the differentiation and function of mature lymphoid cells. We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2. This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation. Although mature T cells are present, the absence of CD25 does affect the differentiation of thymocytes. While displaying normal development of CD2, CD3, CD4, and CD8 expression, CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2.
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PMID:Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. 909 64

The prognostic significance of Bcl-2 protein expression and bcl-2 gene rearrangement in diffuse large cell lymphomas (DLCL) is controversial. Bcl-2 protein expression prevents apoptosis and may have an important role in clinical drug resistance. The presence of a bcl-2 gene rearrangement in de novo DLCL suggests a possible follicle center cell origin and perhaps a distinct clinical behavior more akin to low-grade non-Hodgkin's lymphoma (NHL). The purpose of this study was to determine the impact of Bcl-2 protein expression and bcl-2 gene rearrangement (mbr and mcr) on survival of a cohort of patients with DLCL who were uniformly evaluated and treated with effective chemotherapy. Patients included the original MACOP-B cohort (n = 121) and the initial 18 patients treated with the VACOP-B regimen (total = 139). All patients had advanced-stage disease, were 16 to 70 years old, and corresponded to Working Formulation categories F, G, or H. No patients had prior treatment, discordant lymphoma, or human immunodeficiency virus seropositivity. Paraffin sections from diagnostic biopsies were analyzed for bcl-2 gene rearrangement including mbr and mcr breakpoints by polymerase chain reaction and Bcl-2 protein expression by immunohistochemistry. With a median follow-up of 81 months, overall (OS), disease-free (DFS), and relapse-free survival (RFS) were measured to determine the prognostic significance of these parameters. Analyzable DNA was present in 118 of 139 (85%) cases, with 14 demonstrating a bcl-2 rearrangement (11 mbr, 3 mcr). All 14 of these bcl-2 gene rearrangement-positive cases were found in the 102 patients with a B-cell immunophenotype, but the presence of this rearrangement had no significant influence on survival. Bcl-2 protein expression was interpretable in 116 of 139 (83%) cases, with immunopositivity detected in 54 of 116 (47%). Using a cut-off of greater than 10% Bcl-2 immunopositive tumor cells for analysis, positive Bcl-2 protein expression was seen in 28 of 116 (24%) patients and the presence of this expression correlated with decreased 8-year OS (34% v 60%, P < .01), DFS (32% v 66%, P < .001), and RFS (25% v 59%, P < .001). Bcl-2 protein expression remained significant in multivariate analysis that included the clinical international prognostic index factors and immunophenotype (P < .02). In conclusion, although bcl-2 gene rearrangement status could not be shown to have an impact on outcome, Bcl-2 protein expression is a strong significant predictor of OS, DFS, and RFS in DLCLs.
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PMID:Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma. 920 59

Apoptosis is a physiological process of cell death that occurs as part of normal development and in response to a variety of physiological and pathophysiological stimuli. The effector mechanisms which carry out the death program are well preserved across species and evolution. Apoptosis is important in the immune system, and plays significant roles in the control of the immune response, the deletion of immune cells recognising self-antigens, and cytotoxic killing. Some of the molecular regulators of these processes, such as CD95 and bcl-2 family proteins are the subjects of intense research. Malfunctioning of the immune system may lead to increased or decreased cell death. Conversely, dysregulation of apoptotic pathways themselves may lead to a spectrum of human disease, including autoimmune disease and immunodeficiency.
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PMID:Apoptosis and the immune system. 937 39

There is evidence indicating that autoreactive B cells constitute a substantial part of the B cell repertoire. This autoreactive repertoire secretes the so-called natural autoantibodies characterized by their broad reactivity mainly directed against well-conserved public epitopes. Their germinal origin is suggested by their early appearance during ontogeny, their expression of cross-reactive idiotopes, and structural studies of their sequence. As for the physiological role of the repertoire, it may play a major role as a first barrier of defense. It is presently unknown whether these polyreactive B cells could constitute a pre-immune template which, through an antigen-driven process, may be involved in the production of immune high-affinity antibodies. This autoreactive B cell repertoire frequently undergoes malignant transformation, although there is controversy concerning the reasons accounting for this. It has been postulated that the continuous challenge of this autoreactive repertoire by self-antigens could create propitious conditions for malignant transformation to occur. However, this hypothesis still needs to be substantiated. Chronic lymphocytic leukemia (CLL), the most frequent form of leukemia in western countries, is characterized by constant expression of the CD5 marker and low expression of surface membrane immunoglobulin (Ig) in B lymphocytes. CLL B lymphocyte is frequently committed for natural autoantibody secretion. Despite expressing the Epstein-Barr virus (EBV) receptor CLL B cells cannot be infected by the EBV virus, they overexpress the bcl-2 protein and they are unable to adequately respond when stimulated through the B cell receptor pathway. Autoimmune-associated phenomena are frequently observed in B-cell CLL. These autotoxic manifestations are mainly directed against hematopoietic cells. In most cases, autoantibodies against red blood cells are warm reactive polyclonal IgG. Immune thrombocytopenia is observed in about 2% of cases, but higher frequencies of increased platelet associated Igs have been reported. Pure red cell aplasia and autoantibodies against neutrophils are only rarely observed. This pattern is similar to that observed in primary immunodeficiency syndromes, in which immune thrombocytopenia, autoimmune hemolytic anemia, and pure red cell aplasia are frequently observed. The potential role of T cell defects in inducing autoimmune complications in B-cell CLL has been stressed by recent publications showing increased frequency of autoimmune hemolytic anemia in patients treated with purine nucleoside analogues. However, evidence is presently scarce concerning a functional impairment of T cells after administration of these drugs.
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PMID:Basic biology of autoimmune phenomena in chronic lymphocytic leukemia. 948 25

Common variable immunodeficiency represents the most frequently occurring primary immunodeficiency disorder and is usually detected sporadically in patients with no family history of immunodeficiency. We present the case stories of two monozygote twins, who following a period of decreasing serum immunoglobulins developed primary central nervous system lymphomas. One twin had clinical and paraclinical features mimicking multiple sclerosis. Immunohistochemical investigations on biopsy tissue showed expression of the bcl-2 and p53 gene products, and Epstein-Barr virus (EBV) encoded small RNA's (EBER) indicating latent infection were detected in lymphoma cells using in situ hybridisation techniques. The pathogenetic role of EBV in oncogenesis is discussed.
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PMID:EBV-positive primary central nervous system lymphomas in monozygote twins with common variable immunodeficiency and suspected multiple sclerosis. 949 19

The association of Epstein-Barr virus (EBV) with B-cell lymphoma was examined in 72 human immunodeficiency virus-negative Japanese patients using the polymerase chain reaction (PCR) on DNA obtained from formalin-fixed paraffin-embedded tissues and an in situ hybridization (ISH) technique. EBV-encoded RNA 1 (EBER-1) was detected in 12 of 72 cases (17%); five of 33 cases (15%) of nodal B-cell lymphomas and seven of 39 cases (18%) of extranodal B-cell lymphomas. Three cases of post-bone marrow transplantation and one case of autoimmune disease (Evans syndrome) were included among seven EBER-1 positive extranodal lymphomas. A combined study of immunohistochemistry and EBER-1 revealed that some L26 positive cells were EBER-1 positive. A DNA band was also observed in 13 of 70 examined cases (19%) (four of 33 cases of nodal B-cell lymphomas (12%) and nine of 37 cases of extranodal B-lymphomas (24%)) in the PCR study using primers to detect the Bam HI-W fragment of EBV. In the immunohistochemical study using a monoclonal antibody to the latent membrane protein 1 (LMP-1) of the EBV, one of the EBV-encoded latent gene products, LMP-1, was expressed in six of 34 cases (18%) of extranodal B-lymphomas, but none of the cases with nodal B-cell lymphomas were shown to be LMP-1 positive. Oncoprotein bcl-2 was examined by immunohistochemistry and found to be expressed in seven cases of nodal lymphomas and three cases of extranodal lymphomas, and two of these nodal cases were EBER ISH positive. In EBV serology, only two cases of nodal and one case of extranodal EBER positive B-cell lymphomas revealed a reactivation pattern. In the PCR study using primers to detect the lymphocyte-determined membrane antigen (LYDMA), the same sized monoclonal bands were observed in case 36 in the PCR products from the nose and skin, suggesting the monoclonal proliferation of the tumor. These findings suggested a low incidence of EBV association with B-cell lymphomas unless patients were in an immunologically impaired condition such as post-organ transplantation or autoimmune diseases.
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PMID:Determination of Epstein-Barr virus association with B-cell lymphomas in Japan: study of 72 cases--in situ hybridization, polymerase chain reaction, immunohistochemical studies. 963 83

The bcl-2 protooncogene encodes an inner mitochondrial membrane protein that blocks programmed cell death. There is now increasing evidence that regulation of bcl-2 expression is a determinant of life or death in normal lymphocytes. In this study, we examined bcl-2 expression in lymphocytes from human immunodeficiency virus type 1 (HIV-1)-infected and healthy subjects by flow cytometry. bcl-2 expression was detected in more than 97% of peripheral blood lymphocytes in both healthy and HIV-infected individuals. It was consistently observed that CD4+ lymphocytes from HIV-1-infected individuals with less than 200 CD4+ cells/microliter expressed significantly less bcl-2 than healthy controls. In contrast, bcl-2 expression in CD8+ lymphocytes of these patients was significantly enhanced. No significant alteration of bcl-2 expression was found when lymphocytes of healthy individuals were polyclonally activated in the presence of various regulatory cytokines. Cells undergoing apoptosis showed significantly lower bcl-2 expression than viable cells. Staining of apoptotic cells revealed that lymphocytes from HIV-1-infected subjects were characterized by an increased susceptibility to programmed cell death which was not restricted to a particular lymphocyte subset. Despite significantly different bcl-2 expression in CD4+ and CD8+ lymphocytes of HIV-1-infected individuals with less than 200 CD4+ cells/microliter, no difference could be observed concerning their susceptibility to undergo apoptosis. Therefore, we conclude that sensitivity or resistance to in vitro induction of apoptosis does not directly correlate with bcl-2 expression.
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PMID:Differential expression of bcl-2 and susceptibility to programmed cell death in lymphocytes of HIV-1-infected individuals. 964 32

Epstein-Barr virus (EBV) has been detected in the large majority of HIV-related primary central nervous system lymphomas (PCNSL) suggesting a pathogenetic role of the virus. Unlike HIV-related PCNSL, conflicting data exist with regard to the presence of EBV in non immunodeficiency-related (sporadic) PCNSL. For this reason, a population based material of 41 sporadic PCNSL was analysed for the presence of EBV genome (EBER, BHLF) using RNA in situ hybridisation (RISH). Furthermore, the expression of the gene products of the bcl-2 oncogene and the p53 tumor suppressor gene and the tumor growth fraction reactive with the monoclonal antibody Ki-67 have been evaluated. All cases but two were EBV genome negative. In the two positive cases less than 5% of tumor cells showed EBER positivity. In contrast, more than 75% of cells morphologically belonging to the tumor-cell population stained positively for EBER in two cases of HIV related PCNSL. Immunostaining for the bcl-2 oncoprotein was positive in 28 (72%) of 39 cases examined. In most cases more than 75% of tumor cells showed cytoplasmic expression. Of 37 cases investigated for p53 expression, 21 (57%) stained positively. However, in the large majority of positive cases less than 10% of the neoplastic cells stained. The percentage of Ki-67 positive cells ranged between 10% and 80% with a mean of 50%. The expression of the p53 and bcl-2 oncoproteins and the growth fraction did not have any prognostic impact. We conclude that the EBV genome is rarely detected in sporadic PCNSL, indicating that a pathogenetic role of EBV is unlikely. Like extracerebral B-cell lymphomas a large fraction of PCNSL expresses the p53 and bcl-2 oncoproteins, a feature, however, which does not seem to have prognostic implications.
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PMID:Primary central nervous system lymphomas in immunocompetent individuals: histology, Epstein-Barr virus genome, Ki-67 proliferation index, p53 and bcl-2 gene expression. 966 83

This work aims at characterizing the interplay between human immunodeficiency virus type 1 (HIV-1) and the antiapoptotic cellular protein Bcl-2 responsible for a persistent infection in lymphoblastoid T (J.Jhan) or monocytic (U937) cells. We report that the kinetics of Bcl-2 protein level during the establishment of a chronic infection is biphasic, characterized by a transient decrease followed by restoration to the initial level. The extent and duration of this transient decrease were inversely correlated with the basal level of Bcl-2 as shown by kinetics of Bcl-2 levels in J. Jhan or U937 clones exhibiting different levels of Bcl-2. Using these clones, we also showed that Bcl-2 downregulates HIV-1 replication. Therefore, the cells overexpressing Bcl-2 are characterized by a low viral burden which, in turn, has little effect on the level of this protein. The observed bipasic kinetics is the result of a dual regulation of Bcl-2 induced by HIV-1 infection itself: an upregulation at the transcriptional level of the bcl-2 gene concomitant with a downregulation at the protein level. Convergent data suggest that this downregulation is caused by the oxidative stress induced by the infection itself as shown by the associated modulations of glutathione and thioredoxin levels and by the prevention of these dysregulations by N-acetylcysteine. Altogether, these data indicate that infection first results in a decrease of Bcl-2, permitting an initial boost of replication. Then, as the synthesis at the transcriptional level proceeds, the replication is negatively controlled by Bcl-2 to reach a balance characterized by low virus production and a level of Bcl-2 compatible with cell survival. We suggest that the basal level of Bcl-2, together with infection-inducible transcription factors able to activate bcl-2 gene transcription, is a critical cellular determinant in the tendency toward an acute or a persistent infection.
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PMID:Human immunodeficiency virus induces a dual regulation of Bcl-2, resulting in persistent infection of CD4(+) T- or monocytic cell lines. 981 3

Many viruses, including human immunodeficiency virus type 1 (HIV-1), induce apoptosis and are affected by cellular expression of antiapoptotic genes. We sought to examine the effect of antiapoptotic gene expression on HIV replication by transfecting the promyelomonocytic cell line U937 with the bcl-xl gene to obtain clones of U937 cells that overexpressed bcl-xl (designated U937bcl-xl), a negative control U937 clone transfected with vector alone (designated U937neo) and a clone overexpressing bcl-2 (designated U937bcl-2). After infection with HIV-1, U937neo cells underwent apoptosis four times as frequently as the U937bcl-xl cells. Furthermore, U937bcl-xl cells produced 5-fold less HIV-1 protein than U937neo, whereas U937bcl-2 produced at least 2-fold more p24 than the U937neo control. Transient coexpression of bcl-2 or bcl-xl decreased HIV production and transcription from the HIV LTR. To define the mechanism by which bcl-xl, but not bcl-2, inhibits HIV expression, we examined bcl-2 and bcl-xl expression after HIV infection and CD4 cross-linking. Although HIV-1 infection or cross-linking CD4 led to a decrease in expression of bcl-2, it had no effect on bcl-xl expression. These results provide a mechanism for the resistance of U937bcl-xl transfectants, but not U937bcl-2 transfectants, to HIV-1 replication in monocytic cells in vitro. Therapies that up-regulate bcl-xl expression potentially provide a novel means to decrease the destructiveness of HIV-1.
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PMID:U937 cells overexpressing bcl-xl are resistant to human immunodeficiency virus-1-induced apoptosis and human immunodeficiency virus-1 replication. 1008 20


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