Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progression to AIDS in asymptomatic HIV-infected individuals is characterized by a gradual but progressive loss of CD4+ T cells. While the mechanisms underlying this decline are currently unknown, recent evidence suggests that these cells are abnormally sensitive to apoptosis in response to activation signals. Recent work has implicated downregulation of Bcl-2 with the increased spontaneous apoptosis in lymphocytes from HIV-infected patients. We have evaluated the roles of the apoptosis-protective proteins Bcl-2 and Bcl-x in stimulated PBMC from asymptomatic HIV-infected and HIV-uninfected individuals. We found that Bcl-2 was constitutively expressed in PBMC from both HIV-infected and uninfected samples. However, Bcl-x induction was delayed and responses were decreased in stimulated HIV-infected samples. Additionally, single-cell intracellular staining of Bcl-x revealed a significant inverse correlation between PWM-induced Bcl-x expression and apoptosis (r = -0.695, P = 0.05). This was confirmed at the single-cell level in direct experiments when stimulated cells were sorted based on Bcl-x induction and then measured for apoptosis. Furthermore, low Bcl-x expression was not due to reduced lymphocyte activation following PWM stimulation. Our data indicate that the induction of Bcl-x is markedly impaired in asymptomatic HIV-infected patients and that stimuli which induce inadequate expression of Bcl-x are associated with increased levels of apoptosis in these cells.
 ...
PMID:Impaired induction of the apoptosis-protective protein Bcl-xL in activated PBMC from asymptomatic HIV-infected individuals. 916 4

In the peripheral immune system, apoptosis is involved in the down-regulation of immune reactions, acting as a homeostatic mechanism to limit the expansion of activated lymphocytes, for example in viral diseases. We previously reported that uninfected T lymphocytes from HIV-infected persons were highly prone to in vitro spontaneous apoptosis which was increased following TCR-dependent or independent activation. The present report reviews recent data suggesting that the chronic stimulation of the immune system in HIV infection induces a dysregulation in the expression of molecules involved in cell survival (Bcl-2) or cell death (Fas), promoting an exacerbated peripheral cell death in blood and lymph nodes, possibly contributing to the loss of both functional cytotoxic and helper T lymphocytes in AIDS.
 ...
PMID:Programmed cell death in HIV infection: dysregulation of BCL-2 and Fas pathways and contribution to AIDS pathogenesis. 926 45

Kaposi's sarcoma (KS) is an angioproliferative disease associated with infection by the human herpesvirus-8 (HHV-8). HHV-8 possesses genes including homologs of interleukin-8 (IL-8) receptor, Bcl-2, and cyclin D, which can potentially transform the host cell. However, the expression of these genes in KS tissues is very low or undetectable and HHV-8 does not seem to transform human cells in vitro. In addition, KS may not be a true cancer at least in the early stage. This indicated that besides its transforming potential, HHV-8 may act in KS pathogenesis also through indirect mechanisms. Evidence suggests that KS may start as an inflammatory-angiogenic lesion mediated by cytokines. However, little is known on the nature of the inflammatory cell infiltration present in KS, on the type of cytokines produced and on their role in KS, and whether this correlates with the presence of HHV-8. Here we show that both acquired immunodeficiency syndrome (AIDS)-KS and classical KS (C-KS) lesions are infiltrated by CD8+ T cells and CD14+/CD68+ monocytes-macrophages producing high levels of gamma-interferon (gamma IFN) which, in turn, promotes the formation of KS spindle cells with angiogenic phenotype. gamma IFN, in fact, induces endothelial cells to acquire the same features of KS cells, including the spindle morphology and the pattern of cell marker expression. In addition, endothelial cells activated by gamma IFN induce angiogenic lesions in nude mice closely resembling early KS. These KS-like lesions are accompanied by production of basic fibroblast growth factor, an angiogenic factor highly expressed in primary lesions that mediates angiogenesis and spindle cell growth. The formation of KS-like lesions is upregulated by the human immunodeficiency virus Tat protein demonstrating its role as a progression factor in AIDS-KS. Finally, gamma IFN and HLA-DR expression correlate with the presence of HHV-8 in lesional and uninvolved tissues from the same patients. As HHV-8 infects both mononuclear cells infiltrating KS lesions and KS spindle cells, these results suggest that HHV-8 may elicit or participate in a local immune response characterized by infiltration of CD8+ T cells and intense production of gamma IFN which, in turn, plays a key role in KS development.
 ...
PMID:gamma-Interferon produced by CD8+ T cells infiltrating Kaposi's sarcoma induces spindle cells with angiogenic phenotype and synergy with human immunodeficiency virus-1 Tat protein: an immune response to human herpesvirus-8 infection? 944 57

The EBV plays a major role in the development of lymphoproliferative disorders in immunosuppressed patients. After organ transplantation most of lymphoproliferative disorders associated with EBV are polymorphic, with various expression of clonality. The pattern of EBV latency genes expression is rather the same as in lymphoblastoid cells lines and the EBV infected cells strongly expressed activation and adhesion molecules in most cases. In AIDS-related lymphomas the frequency of EBV as well as the expression of latency genes are related to the localization and to the histological subtypes. While EBV is observed in 30 to 50% of cases of Burkitt's lymphomas occurring the early stage of AIDS, its association in primary brain lymphomas and immunoblastic lymphomas developed in the late stage is observed in nearly all cases as well as in Hodgkin's disease. In primary brain lymphomas, the high expression of LMP-1 protein is correlated to the expression of BCL2 oncoprotein suggesting a transactivation of bcl2 by LMP-1 as it was reported in vitro. In non overt immunosuppressed patients the role of EBV is less clearly established, particularly in Burkitt's lymphoma where EBV is now considered as a cofactor. In B-cell lymphoma EBV is detected in about 5% of cases except in peculiar situations such as in lymphoma occurring in pleural cavity after longstanding pleural chronic inflammation and in Richter's syndrome with Reed-Sternberg-like cells. In peripheral T-cell lymphomas, EBV is observed in about 25% of cases, but its frequency varies with the histology and the localisation. EBV is present in nearly all cases of angio-immunoblastic type and in the nasal lymphoid proliferations developed from the NK cells. Detected in 30 to 80% in the Reed-Sternberg cells of Hodgkin's disease cases, the pathogenic significance of EBV remains to be determined in this disease.
 ...
PMID:[Role of Epstein-Barr Virus in lymphoproliferative disorders]. 945 45

We studied overexpression of p53, Bcl-2, Bcl-6, c-Myc and Mdm2 proteins by immunohistochemistry for a total of 27 primary central nervous system B cell lymphomas (CNS lymphomas) in immunocompetent patients and one CNS lymphoma in an AIDS patient. The expression of Epstein-Barr (EB) virus-encoded small RNA-1 (EBER-1) was also analysed using in situ hybridisation. Overexpression (more than 20% of cells stained) of p53 protein was detected in 8 of 27 immunocompetent cases (30%); 6 cases showed a nuclear stain and 2 cases showed cytoplasmic stain (nuclear exclusion). Strong Bcl-2 or Bcl-6 immunoreactivity suggestive of overexpression was seen, respectively, in 5 (19%) and 6 (22%) cases; 2 cases were positive for both immunoreactivities. Interestingly, overexpression of Bcl-2 or Bcl-6 was not seen in the cases which showed p53 overexpression (P < 0.03; chi-square test). EBER-1 expression was not detected in any of the 27 immunocompetent cases, but was found in the AIDS-related CNS lymphoma, which also showed an overexpression of Bcl-6, but not Bcl-2. None of the cases showed c-Myc or Mdm2 overexpression. Taken together, it is suggested that CNS lymphoma in immunocompetent hosts is a distinct disease that has a different molecular profile from those of systemic lymphoma and/or AIDS-related CNS lymphoma.
 ...
PMID:Expression of oncogenic molecules in primary central nervous system lymphomas in immunocompetent patients. 960 May 97

Apoptosis is an essential and highly conserved mode of cell death that is important for normal development, host defense and suppression of oncogenesis. Faulty regulation of apoptosis has been implicated in degenerative conditions, vascular diseases, AIDS and cancer. Among the numerous proteins and genes involved, members of the Bcl-2 family play a central role to inhibit or promote apoptosis. In this article, we present up-to-date information and recent discoveries regarding biochemical functions of Bcl-2 family proteins, positive and negative interactions between these proteins, and their modification and regulation by either proteolytic cleavage or by cytosolic kinases, such as Raf-1 and stress-activated protein kinases. We have critically reviewed the functional role of caspases and the consequences of cleaving key substrates, including lamins, poly(ADP ribose) polymerase and the Rb protein. In addition, we have presented the latest Fas-induced signalling mechanism as a model for receptor-linked caspase regulation. Finally, the structural and functional interactions of Ced-4 and its partial mammalian homologue, apoptosis protease activating factor-1 (Apaf-1), are presented in a model which includes other Apafs. This model culminates in a caspase/Apaf regulatory cascade to activate the executioners of programmed cell death following cytochrome c release from the mitochondria of mammalian cells. The importance of these pathways in the treatment of disease is highly dependent on further characterization of genes and other regulatory molecules in mammals.
 ...
PMID:Mechanisms controlling cellular suicide: role of Bcl-2 and caspases. 964 23

Peripheral blood lymphocytes (PBLs) from 51 HIV-1-seropositive subjects with different levels of HIV-1 replication and 20 healthy blood donors were examined for the expression of the antiapoptotic Bcl-2 protein. All the plasma samples from HIV-1 patients were characterized for the presence of HIV-1 p24 and HIV, RNA viral load. Bcl-2 protein expression in fresh peripheral blood lymphocytes was studied by different tests, including Western blot and indirect immunofluorescence techniques. Direct immunofluorescence staining, revealed by flow cytometry, was applied to quantify the number of specific anti-Bcl-2 antibody epitope binding sites, thus extrapolating the relative number of Bcl-2 into the cells. The results indicate that the expression of Bcl-2 protein is significantly lower in peripheral blood lymphocytes of HIV-1-seropositive patients showing high levels of viral replication, detected by means of HIV-1 p24 and RNA viral load, with respect to HIV-1 patients with low levels of virus replication and healthy blood donors. The clear-cut inverse correlation between viral replication and Bcl-2 expression reinforces the view that HIV-1-mediated apoptosis probably represents a key mechanism in AIDS pathogenesis.
 ...
PMID:High levels of HIV-1 replication show a clear correlation with downmodulation of Bcl-2 protein in peripheral blood lymphocytes of HIV-1-seropositive subjects. 970 Jun 35

Extranodal oral lymphomas, seen with increasing frequency in HIV infection, may have dysfunctional apoptotic mechanisms that favor tumor progression. The purpose of this study was to evaluate extranodal lymphomas from HIV-positive patients for expression of apoptosis-associated proteins. Correlations were made with 10 histologically comparable extranodal lymphomas from HIV-negative patients and 6 hyperplastic lymph nodes from otherwise healthy young adults. Formalin-fixed tissue sections were immunohistochemically stained for apoptosis-associated proteins (Bcl-2, Bcl-x, Bax, Bak, p53, MDM2, BHRF). In situ hybridization was also done on deparaffinized sections for Epstein-Barr virus EBER mRNA. Eighteen consecutive oral lymphomas were studied in HIV/AIDS-positive patients. Four of 5 intermediate-grade lymphomas expressed Bcl-2 to a greater degree than did high-grade lymphomas (4 of 13). Most lymphomas were positive for Bcl-x and Bax, and few expressed Bak. The staining patterns for these proteins were similar to those seen in HIV-negative patients. Staining patterns were relatively consistent in the hyperplastic lymph nodes, whereas such patterns were irregular in lymphomas. Positive p53 staining was seen in 11 of 18 HIV-positive cases; 9 of these were also MDM2-positive. Double stains suggested that both p53 and MDM2 proteins were expressed in the same cells in these nine cases. Epstein-Barr virus-EBER mRNA was detected in 14 of 18 cases and in 3 of 10 cases from HIV-negative patients. BHRF staining was evident in only a few cells of three HIV-positive lymphomas. The irregular expression of Bcl-2, Bcl-x, Bax, and Bak in oral lymphomas indicates dysfunctional apoptotic mechanisms in these tumors. Bcl-2 staining differs with tumor grade. Positive staining for p53 and MDM2 proteins is a notable feature of lymphomas in HIV-positive patients and may relate to binding of MDM2 to wild-type p53. Epstein-Barr virus is more commonly associated with oral lymphomas in HIV-positive patients, although the Epstein-Barr virus-produced protein BHRF, which has Bcl-2-like activity, is minimally expressed.
 ...
PMID:Apoptosis-associated proteins in oral lymphomas from HIV-positive patients. 972 96

Apoptosis is a morphologically distinct form of programmed cellular death that plays a central role during embryogenesis, tissue homeostasis, and to remove not necessary or potentially dangerous cells. Moreover, disregulation of genes mediating or modulating apoptosis contributes to the pathogenesis of a number of human diseases, including cancer, autoimmune diseases, neurodegenerative disorders, viral infections and acquired immunodeficiency syndrome. A number of genes and molecules promoting or protective against cell death is at present-day known and an important information about the external and internal signals involved in stimulation and suppression of apoptosis is also emerging. In the intracellular pathway of the death deregulation of [Ca2+](i) plays a pivotal role. Increased ionized intracellular calcium stimulates both the activation of enzymes (protein kinases, endonucleases, proteases and phospholipases) and plasma membrane K+ channels. This calcium-mediated activation leads to morphostructural changes, such as cell shrinkage, cytoplasmatic blebbing, nuclear chromatin condensation and DNA degradation into oligonucleosomal fragments. At least some genes of the cell death pathway have been conserved throughout animal evolution; ced-3 e ced-9 that regulate the initiation of cellular suicide in the nematode Caenorhabditis elegans are homologous to genes that in mammalian cells are thought to play a similar role (interleukin-1 beta converting enzyme [ICE] family, Bcl-2). It is possible to suppose that these regulators could constitute a target for treatment of disorders related with disregulation of apoptosis.
 ...
PMID:[Genes, molecules, and mechanisms regulating programmed cell death]. 973 54

The pathogenesis of Kaposi's sarcoma (KS), a tumor of probable vascular origin, remains an enigma. It is still unclear whether KS is a true malignancy or whether it represents a reactive polyclonal process. Using both an immunohistochemical and an immunoblot approach, we found that cells derived from KS lesions express significant levels of Bcl-2, a protein known to prolong cellular viability and to antagonize apoptosis. Bcl-2 expression was found in AIDS-related KS-derived cells, as well as in cells derived from iatrogenic and sporadic KS, indicating that Bcl-2 upregulation may be important in the pathogenesis of KS regardless of its epidemiologic form. By contrast, fibroblasts and dermal microvascular endothelial, cells which are the probable vascular progenitors of KS cells, expressed low levels of Bcl-2. The expression of Bcl-2 in KS-derived cells was associated with a long-term survival in serum-deprived conditions, a situation that has been shown to induce apoptosis in various cell types. Incubation of fibroblasts or of dermal microvascular endothelial cells with KS cell-free supernatants did not enhance Bcl-2 expression, suggesting that Bcl-2 expression is not mediated by an agent released by KS cells. Analogously, KS supernatants failed to promote the viability of fibroblasts and of dermal microvascular endothelial cells cultured in serum-free conditions. Our findings suggest that the spindle cells derived from KS have a survival advantage and may adequately represent the tumor cells of KS.
 ...
PMID:Overexpression of Bcl-2 in Kaposi's sarcoma-derived cells. 974 Feb 22


<< Previous 1 2 3 4 5 6 7 8 Next >>