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)

Murine AIDS (MAIDS) induced by infection of C57BL/6 mice with a mixture of retroviruses known as LP-BM5 is characterized by lymphadenopathy, splenomegaly, and T and B cell dysfunction. By labeling with bromodeoxyuridine in vivo, we found vigorous CD4 T cell proliferation during the initial stages of infection, yet a loss in their ability to function both in vivo and in vitro. In addition, a significant fraction of the CD4 T cell population in infected mice undergoes spontaneous apoptosis in vivo. Upon in vitro stimulation with anti-CD3 plus PMA, anergic CD4 T cells from mice with MAIDS fail to progress through the cell cycle (G0/G1 arrest), and a fraction of the cells undergoes apoptosis. The addition of IL-2 along with TCR-mediated stimulation not only fails to rescue CD4 T cells from apoptosis, but enhances activation-induced cell death. To further understand the regulation of the suicide pathway(s) of anergic CD4 T cells vs the cytokine synthesis pathway(s) of normal CD4 T cells, we evaluated their expression of Bcl-2 protein. As infection progresses, the expression of Bcl-2 among CD4 T cells declines and drops further when CD4 T cells are restimulated through the TCR in vitro. These results suggest that this CD4 T cell immunodeficiency in MAIDS includes a TCR-induced program of activation-induced cell death and an uncoupling from cytokine synthesis pathways and proliferation of CD4 T cells. The decline in Bcl-2 expression may be in part responsible for this reprogramming.
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PMID:TCR triggering of anergic CD4 T cells in murine AIDS induces apoptosis rather than cytokine synthesis and proliferation. 875 10

Fas is a cell-surface protein belonging to the tumor necrosis factor (TNF) receptor family, whereas the Fas ligand (FasL) is a member of the TNF family. FasL binds to Fas, which results in target cell apoptosis. A family of cysteine proteases is sequentially activated to proceed the Fas-induced apoptosis, whereas Bcl-2 inhibits the process. FasL is expressed in activated T cells and natural killer (NK) cells, and works as an effector of these cytotoxic cells to remove the cells infected by virus, or cancer cells. The Fas system is also involved in peripheral clonal deletion, and/or the activation-induced suicide of T cells to down-regulate the immune reaction. Mouse mutations of lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld), which cause lymphadenopathy and splenomegaly, and accelerate autoimmune disease, are loss-of-function mutations in the Fas and FasL genes, respectively. Moreover, the Fas-null mice established by gene targeting showed hyperplasia in the liver, suggesting that the Fas system is involved in turn-over of senescent hepatocytes.
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PMID:A death factor--the other side of the coin. 895 Apr 63

Splenic lymphoma with villous lymphocytes (SLVL) is a low grade lymphoproliferation characterized by a massive splenomegaly, an absence of lymphadenopathy and the presence in the peripheral blood of atypical B-lymphocytes with hairy-cell appearance. We have studied the morphological, immunological and molecular characteristics of 3 cases of SLVL. SLVL presented on blood smears characteristic irregularities of the plasma membrane consisting in thin and short villi unevenly distributed. The main phenotype was CD5-, CD11c+, and CD25-, but individual SLVL cases can not be identified by using immunohistochemical criteria alone. Clonal rearrangements of the immunoglobulin heavy chain gene were found in all 3 cases and in one case presented a bcl2-JH rearrangement. SLVL are clonal B-cell lymphoproliferations and can be associated with t(14; 18) translocation.
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PMID:[Splenic lymphoma with villous lymphocytes: morphologic, immunologic and molecular study. Report of three cases]. 917 20

Murine gamma-herpesvirus 68 (MHV-68) is a natural pathogen of small rodents and insectivores (mice, voles and shrews). The primary infection is characterized by virus replication in lung epithelial cells and the establishment of a latent infection in B lymphocytes. The virus is also observed to persist in lung epithelial cells, dendritic cells and macrophages. Splenomegaly is observed two weeks after infection, in which there is a CD4+ T-cell-mediated expansion of B and T cells in the spleen. At three weeks post-infection an infectious mononucleosis-like syndrome is observed involving a major expansion of Vbeta4+CD8+ T cells. Later in the course of persistent infection, ca. 10% of mice develop lymphoproliferative disease characterized as lymphomas of B-cell origin. The genome from MHV-68 strain g2.4 has been sequenced and contains ca. 73 genes, the majority of which are collinear and homologous to other gamma-herpesviruses. The genome includes cellular homologues for a complement-regulatory protein, Bcl-2, cyclin D and interleukin-8 receptor and a set of novel genes M1 to M4. The function of these genes in the context of latent infections, evasion of immune responses and virus-mediated pathologies is discussed. Both innate and adaptive immune responses play an active role in limiting virus infection. The absence of type I interferon (IFN) results in a lethal MHV-68 infection, emphasizing the central role of these cytokines at the initial stages of infection. In contrast, type II IFN is not essential for the recovery from infection in the lung, but a failure of type II IFN receptor signalling results in the atrophy of lymphoid tissue associated with virus persistence. Splenic atrophy appears to be the result of immunopathology, since in the absence of CD8+ T cells no pathology occurs. CD8+ T cells play a major role in recovery from the primary infection, and also in regulating latently infected cells expressing the M2 gene product. CD4+ T cells have a key role in surveillance against virus recurrences in the lung, in part mediated through 'help' in the genesis of neutralizing antibodies. In the absence of CD4+ T cells, virus-specific CD8+ T cells are able to control the primary infection in the respiratory tract, yet surprisingly the memory CD8+ T cells generated are unable to inhibit virus recurrences in the lung. This could be explained in part by the observations that this virus can downregulate major histocompatibility complex class I expression and also restrict inflammatory cell responses by producing a chemokine-binding protein (M3 gene product). MHV-68 provides an excellent model to explore methods for controlling gamma-herpesvirus infection through vaccination and chemotherapy. Vaccination with gp150 (a homologue of gp350 of Epstein-Barr virus) results in a reduction in splenomegaly and virus latency but does not block replication in the lung, nor the establishment of a latent infection. Even when lung virus infection is greatly reduced following the action of CD8+ T cells, induced via a prime-boost vaccination strategy, a latent infection is established. Potent antiviral compounds such as the nucleoside analogue 2'deoxy-5-ethyl-beta-4'-thiouridine, which disrupts virus replication in vivo, cannot inhibit the establishment of a latent infection. Clearly, devising strategies to interrupt the establishment of latent virus infections may well prove impossible with existing methods.
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PMID:Natural history of murine gamma-herpesvirus infection. 1131 14

B-cell chronic lymphocytic leukemia (B-CLL) follows heterogeneous clinical courses, and several biological parameters need to be added to the current clinical staging systems to predict which patients will experience an indolent or an aggressive outcome. This study analyzed CD38 expression by flow cytometry and soluble APO1/Fas (sAPO1/Fas), Bcl-2 (sBcl-2), and CD23 (sCD23) proteins by immunoenzymatic methods to evaluate their effect on the clinical course of 168 unselected B-CLL patients. Intermediate/high risk modified Rai stages were characterized by a higher CD38(+) B-cell number (P =.0002) and higher sCD23 levels (P <.0001). Moreover, CD38(+) B-cell percentages were significantly and directly associated both with beta(2)-microglobulin and sCD23 concentrations (P <.0001 and P =.002, respectively). Both a higher tumor burden (lymphadenopathy/splenomegaly) and a lymphocyte doubling time less than 12 months were significantly associated with higher CD38(+) percentages (P <.0001 and P =.0001, respectively). With regard to clinical outcome, progression-free survival was significantly longer (75% versus 37% at 5 years; P =.00006) in patients with lower CD38(+) B-cell percentages. Furthermore, the risk of partial or no response to fludarabine increased with increasing CD38 expression (P =.003), and a shorter overall survival (50% versus 92% at 8 years; P <.00001) characterized patients with more than 30% CD38(+) B-cell number. The predictive value of CD38 expression was maintained among the patients within the Rai intermediate risk group and was confirmed in multivariate analysis. Thus, the percentage of CD38(+) B cells appears to be an accurate predictor of clinical outcome and therefore could be used to indicate when more novel chemotherapeutic approaches are needed.
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PMID:Clinical significance of CD38 expression in chronic lymphocytic leukemia. 1167 31

Bak and Bax are required and redundant regulators of an intrinsic mitochondrial cell death pathway. To analyze this pathway in T cell development and homeostasis, we reconstituted mice with Bak(-/-)Bax<(-/-) hematopoietic cells. We found that the development and selection of Bak(-/-)Bax(-/-) thymocytes was disrupted, with altered representation of thymic subsets and resistance to both death-by-neglect and antigen receptor-induced apoptosis. Elimination of Bak(-/-)Bax(-/-) T cells that responded to endogenous superantigen was also reduced. Despite more efficient early reconstitution and apoptotic resistance of Bak(-/-)Bax(-/-) thymocytes, thymic cellularity declined over time. Reduced thymic cellularity resulted from a progressive cessation of thymopoiesis. However, animals developed splenomegaly as a result of accumulated memory T cells that were not deleted after antigen-driven expansion. These data indicate that Bak and Bax are required for thymic selection and peripheral lymphoid homeostasis and suggest that thymopoiesis can be negatively regulated by the accumulation of cells that would normally be eliminated by pro-apoptotic Bcl-2-related genes.
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PMID:Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. 1235 62

The Bcl-2 antisense oligonucleotide (AS-ODN) G3139 chemosensitizes human malignancies by downregulating the antiapoptotic protein Bcl-2. Because G3139 contains two potential immunostimulatory CpG motifs, we asked if immune stimulation contributes to the antitumor activity observed previously. 5'-Methylation of cytosines in CpG motifs abrogates immune stimulation by oligonucleotides. We, therefore, studied the antitumor and immunostimulatory potential of G3139 vs. an identical oligonucleotide, except for methylation of cytosines in the two CpG motifs (G4232). In a human melanoma SCID mouse xenotransplantation model, G3139 or G4232 was administered by continuous subcutaneous (s.c.) or bolus intraperitoneal (i.p.) infusion. Both G3139 and G4232 significantly reduced tumor growth by about one third relative to the saline-treated group. Furthermore, we noted a similar downregulation of Bcl-2 expression and increase in tumor cell apoptosis caused by G3139 and G4232 compared with saline controls. However, mice treated with G3139 had a pronounced increase in spleen weight and interleukin-12 (IL-12) plasma levels relative to mice treated with either G4232 or saline. Splenomegaly and elevated IL-12 plasma levels suggest that G3139 can be immunostimulatory. However, there is clear evidence that the antitumor effect of G3139 in this model appears to be a Bcl-2 antisense effect that is independent of immune stimulation, as G3139 and its immune-silent counterpart G4232 caused similar tumor suppression and apoptosis induction.
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PMID:Antitumor effect of G3139 Bcl-2 antisense oligonucleotide is independent of its immune stimulation by CpG motifs in SCID mice. 1256 10

Transgenic mice overexpressing in B lymphocytes either Bcl-2 or a TNF receptor-associated factor (TRAF)2 mutant lacking the N-terminal RING and zinc finger domains located at the N terminus of the molecule (TRAF2DN), which mimics TRAF1, developed lymphadenopathy and splenomegaly due to polyclonal B cell expansion. Remarkably, TRAF2DN/Bcl-2 double-transgenic mice contained B cell populations similar to those observed in TRAF2DN mice. However, over time, they developed severe splenomegaly and lymphadenopathy, and most animals also developed leukemia, pleural effusion, and, in some cases, ascites associated with monoclonal and oligoclonal B cell neoplasms. The life span of TRAF2DN/Bcl-2 mice was markedly reduced compared with Bcl-2 and TRAF2DN single-transgenics or wild-type littermates. The expanded B cell population of TRAF2DN/Bcl-2 double-transgenic mice was primarily comprised of small/medium-size noncycling B220(M)/IgM(H)/IgD(L)/CD21(L)/CD23(NULL)/CD11b(+)/CD5+ cells that were Bcl-6-negative, consistent with a B-1 phenotype. The cells also expressed high levels of CD54 and other adhesion molecules. In vitro, these B cells showed comparable proliferation rates to those of wild-type counterparts but exhibited markedly increased survival and were resistant to apoptosis induced by chemotherapeutic agents and glucocorticoids. Histopathologic features were consistent with mouse small B cell lymphoma progressing to leukemia with many similarities to human chronic lymphocytic leukemia. Given that many human chronic lymphocytic leukemias overexpress TRAF1 and Bcl-2, our findings suggest that cooperation between Bcl-2 and TRAF pathways contributes to the development of this type of leukemia.
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PMID:TNF receptor-associated factor (TRAF) domain and Bcl-2 cooperate to induce small B cell lymphoma/chronic lymphocytic leukemia in transgenic mice. 1554 99

Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). The protein is thought to be responsible for maintaining the viability of malignant lymphoid cells and may contribute to chemotherapy and radiotherapy resistance. Previous studies have shown that reduction of bcl-2 expression by antisense therapy sensitizes cells to chemotherapy-induced apoptosis. In vitro, the Bcl-2 antisense drug oblimersen sodium (Genasense, previously known as G3139) enhances the apoptotic response in CLL cells to fludarabine (Fludara), corticosteroids, alemtuzumab (Campath), and rituximab (Rituxan). A phase I trial in patients with refractory/relapsed CLL showed that patients with CLL were more sensitive to oblimersen than patients with solid tumors. The maximum tolerated oblimersen dose was 3 mg/kg/d, and the most common dose-limiting reaction was hypotension, frequently in association with high spiking fever. In this study, oblimersen displayed limited single-agent activity, including tumor lysis syndrome, transient decreases in circulating CLL cells, and reduction of splenomegaly and size of lymph nodes. Major responses were observed in 9% of patients. Subsequently, a phase III trial evaluating fludarabine and cyclophosphamide with or without oblimersen (3 mg/kg/d for 7 days) was initiated in patients with relapsed or refractory CLL. This trial recently completed accrual of 241 patients.
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PMID:Potential therapeutic applications of oblimersen in CLL. 1565 Nov 75

Although myc and bcl-2 synergize in tumor development, particularly lymphomagenesis, it is not known whether endogenous bcl-2 is required for myc-induced tumorigenesis. To investigate the role of endogenous Bcl-2 in myc-induced lymphomagenesis, we bypassed the early death of Bcl-2-deficient mice by reconstituting lethally irradiated wild-type (wt) mice with a hematopoietic system from fetal liver-derived stem cells of Emu-myc/bcl-2(-/-) or control Emu-myc transgenic embryos. In premalignant (healthy) recipients, loss of Bcl-2 caused a moderate decrease in pre-B and immature B cells, and a dramatic reduction of mature B lymphocytes expressing the Emu-myc transgene. Furthermore, cultured preneoplastic Emu-myc/bcl-2(-/-) mature B cells displayed accelerated apoptosis compared with Emu-myc B cells. However, despite the striking reduction in B-cell numbers in vivo, ablation of endogenous Bcl-2 did not prevent or even delay development of Emu-myc lymphoma. Moribund mice presented with similar degrees of splenomegaly, blood leukocyte numbers, and tumor dissemination at death. These findings demonstrate that the initiation, development, continued growth, and severity of Emu-myc lymphoma do not depend upon endogenous Bcl-2, nor upon the total number of B lymphoid cells driven by the Emu-myc transgene. These results have implications for the treatment of hematopoietic tumors, particularly those that are not caused by Bcl-2 overexpression.
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PMID:Endogenous bcl-2 is not required for the development of Emu-myc-induced B-cell lymphoma. 1731 59


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