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 outcome of virus infection depends on viral and host factors. The interactions between flaviviruses and their target cells must be investigated if we are to understood the pathogenicity of these RNA viruses. Host cells are thought to respond to viral infection by initiation of apoptotic cell death. Apoptosis is an active process of cellular self-destruction with distinctive morphological and biochemical features. There is mounting evidence that dengue (DEN) virus can trigger the host cell to undergo apoptosis in a cell-dependent manner. Virally induced apoptosis contributes directly to the cytopathogenic effects of DEN virus in cultured cells. The induction of apoptosis involves the activation of intracellular signaling systems. Although the underlying molecular processes that trigger apoptosis are not well characterized, our knowledge regarding the cellular mechanisms and viral determinants of the outcome of DEN virus infection of target cells is improving. The cellular factors that regulate cell death, such as Bcl-2 family members, can modulate the outcome of DEN virus infection in cultured cells. Apoptosis inhibitors delay DEN virus-induced apoptosis, thereby providing a suitable environment for the virus. During DEN virus infection, cell death is also modulated by the virulence of the infecting strains. The purpose of this review is to present recent information on the cellular mechanisms and viral proteins associated with apoptosis in response to DEN virus. This knowledge may provide new insights into the viral pathogenicity.
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PMID:Mechanisms of dengue virus-induced cell death. 1468 94

A balance between proliferation and cell death is critical for achieving desirable high cell densities in mammalian cell culture. In this study, we evaluate a recently discovered anti-apoptotic gene, aven, and examine its effectiveness alone and in combination with a member of the Bcl-2 family, bcl-xL. The commercially popular cell line, Chinese hamster ovary (CHO), was genetically modified to constitutively express aven, bcl-xL, and the two genes in combination. Cells were exposed to several model insults that simulate severe bioreactor environments, including serum deprivation, spent medium, and Sindbis virus infection, as well as staurosporine, a known chemical inducer of apoptosis. CHO cells exhibited DNA fragmentation, a hallmark of apoptosis, after exposure to these model insults. After exposure to serum deprivation, 4- and 5-day spent medium, and staurosporine, cells expressing Aven provided limited protection against cell death when compared with the protection afforded by cells expressing Bcl-xL alone. However, the highest survival levels for all insults were achieved when Aven was expressed in combination with Bcl-xL. In fact, Aven appeared to act synergistically to enhance the protective function of Bcl-xL for several insults, because the protective function of the two genes expressed together in one cell line often exceeded the additive protective levels of each anti-apoptosis gene expressed alone. Surprisingly, Aven expression provided a mildly pro-apoptotic response in CHO isolates infected with Sindbis virus. However, CHO cells expressing both Bcl-xL and Aven showed protection against Sindbis virus infection due to the inhibitory properties of the bcl-xL anti-apoptosis gene. This study shows that combinatorial anti-apoptosis cell engineering strategies may be the most effective mechanisms for providing extended protection against cell death in mammalian cell culture.
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PMID:Aven and Bcl-xL enhance protection against apoptosis for mammalian cells exposed to various culture conditions. 1496

IL-15 is known to be critical in the homeostasis of Ag-specific memory CD8(+) T cells following acute viral infection. However, little is known about the homeostatic requirements of memory CD8(+) T cells during a latent viral infection. We have used the murine gammaherpesvirus-68 (MHV-68) model system to investigate whether IL-15 is necessary for the maintenance of memory CD8(+) T cells during a latent viral infection. IL-15 is not essential either for the initial control of MHV-68 infection or for the maintenance of MHV-68-specific memory CD8(+) T cells. Even at 140 days postinfection, the proportion of CD8(+) T cells recognizing the MHV-68 epitopes were the same as in control mice. The maintenance of these memory CD8(+) T cells was attributable to their ability to turn over in vivo, probably in response to the presence of low levels of Ag. IL-15(-/-) mice had a significantly higher turnover rate within the virus-specific memory CD8(+) T cell population, which was the result of increased levels of viral gene expression rather than an increase in viral load. These cells did not accumulate in the spleens of the IL-15(-/-) mice due to an increased sensitivity to apoptosis as a result of decreased Bcl-2 levels. Intriguingly, memory CD8(+) T cells from latently infected mice failed to undergo homeostatic proliferation in a naive secondary host. These data highlight fundamental differences between memory CD8(+) T cells engaged in active immune surveillance of latent viral infections vs memory CD8(+) T cells found after acute viral infections.
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PMID:IL-15-independent proliferative renewal of memory CD8+ T cells in latent gammaherpesvirus infection. 1529 89

Interleukin (IL)-7 receptor (R) signaling is essential for T and B lymphopoiesis by promoting proliferation, differentiation, and survival of cells. Mice lacking either IL-7 or the IL-7Ralpha chain have abnormally low numbers of immature as well as mature T and B lymphocytes. Transgenic expression of the apoptosis inhibitor Bcl-2 rescues T cell development and function in IL-7Ralpha-deficient mice, indicating that activation of a proapoptotic Bcl-2 family member causes death of immature and mature T cells. BH3-only proteins such as Bim, which are distant proapoptotic members of the Bcl-2 family, are essential initiators of programmed cell death and stress-induced apoptosis. We generated Bim/IL-7Ralpha double deficient mice and found that loss of Bim significantly increased thymocyte numbers, restored near normal numbers of mature T cells in the blood and spleen, and enhanced cytotoxic T cell responses to virus infection in IL-7Ralpha-/- mice. These results indicate that Bim cooperates with other proapoptotic proteins in the death of IL-7-deprived T cell progenitors in vivo, but is the major inducer of this pathway to apoptosis in mature T cells. This indicates that pharmacological inhibition of Bim function might be useful for boosting immune responses in immunodeficient patients.
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PMID:Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice. 1550 23

In this study, we show that Bcl-2, one of the most important antiapoptotic agents, is expressed in a phase-dependent manner in the human adherent monocytes after vaccinia virus infection, reflecting the viral infection stages. Early viral infection induced Bcl-2 expression in a level higher than in control cells. At 14 h post-infection (p.i.), the Bcl-2 level measured in the whole cell extracts dramatically decreased, followed by the increase at 24 h p.i. The levels of active dephosphorylated Bcl- 2 protein present in the cells reflected the gene expression character, but were much lower than in case of a heat shock. The dramatic increase of Bcl-2 protein level in the nuclear fraction at 4 h p.i. was observed. Changes in Bcl-2 mRNA content in elutriated human blood monocytes isolated from the same donor showed different kinetics, increasing up to 12 h p.i. and diminishing to undetectable level at 24 h p.i. concomitantly with a severe increase in the number of dead cells. The results indicate that virally infected adherent monocytes remain resistant to apoptosis, while freshly isolated monocytes undergo apoptotic cell death. These results throw new light on the apoptotic mechanism in the monocyte-derived cells after vaccinia virus infection in vitro.
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PMID:Changes in Bcl-2 expression in vaccinia virus-infected human peripheral blood monocytes. 1580 67

Vesicular Stomatitis Virus (VSV) has been shown to induce apoptosis in a caspase-dependent manner, but the precise apoptotic pathway remains unknown. We found that caspases 9 and 3, but not caspase 8, were activated during VSV-induced apoptosis in infected Vero cells. Since caspase 9 is related to the mitochondrial apoptotic pathway, we analyzed some mitochondrial events such as changes in the mitochondrial transmembrane potential (Deltapsim) and mitochondrial release of apoptogenic proteins such as cytochrome c and the apoptosis inducing factor (AIF). We found that VSV infection triggers the dissipation of the Deltapsim and the release of both cytochrome c and AIF from the mitochondrial intermembrane space very early in the VSV infection. These results indicate that the trigger of apoptosis in VSV-infected cells occurs through the early activation of the mitochondrial apoptotic pathway. On the other hand, intracellular levels of the anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, and the pro-apoptotic protein Bax, were assessed during viral infection. These analyses showed that as viral infection proceeded, the cellular level of Bcl-xL decreased, while the levels of Bax and Bcl-2 remained unaffected. The significance of the Bcl-xL modulation is also discussed.
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PMID:Early activation of the mitochondrial apoptotic pathway in Vesicular Stomatitis virus-infected cells. 1582 14

Flaviviruses such as dengue virus (DEN) and Japanese encephalitis virus (JEV) are medically important in humans. The lipid kinase, phosphatidylinositol 3-kinase (PI3K) and its downstream target Akt have been implicated in the regulation of diverse cellular functions such as proliferation, and apoptosis. Since JEV and DEN appear to trigger apoptosis in cultured cells at a rather late stage of infection, we evaluated the possible roles of the PI3K/Akt signaling pathway in flavivirus-infected cells. We found that Akt phosphorylation was noticeable in the JEV- and DEN serotype 2 (DEN-2)-infected neuronal N18 cells in an early, transient, PI3K- and lipid raft-dependent manner. Blocking of PI3K activation by its specific inhibitor LY294002 or wortmannin greatly enhanced virus-induced cytopathic effects (CPEs), even at an early stage of infection, but had no effect on virus production. This severe CPE was characterized as apoptotic cell death as evidenced by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining and cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Mechanically, the initiator and effector caspases involved are mainly caspase-9 and caspase-6, since only a pan-caspase inhibitor and the inhibitors preferentially target caspase-9 and -6, but not the ones antagonizing caspase-8, -3, or -7 alleviated the levels of PARP cleavage after virus infection and PI3K blockage. Furthermore, Bcl-2 appears to be a crucial mediator downstream of PI3K/Akt signaling, since overexpression of Bcl-2 reduced virus-induced apoptosis even when PI3K activation was repressed. Collectively, our results suggest an anti-apoptotic role for the PI3K/Akt pathway triggered by JEV and DEN-2 to protect infected cells from early apoptotic cell death.
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PMID:Flavivirus activates phosphatidylinositol 3-kinase signaling to block caspase-dependent apoptotic cell death at the early stage of virus infection. 1595 83

Prevention, improved screening, and better treatment regimens have improved cancer incidence and mortality in the last decade. Chemoradiation continues to cause high morbidity in patients undergoing treatment. DNA therapeutics have the potential to modify the genes that cause tumor progression in order to produce a response that is tumor-specific, efficacious and systemic without toxicity to normal cells. The most widely used and most experimentally advanced DNA therapeutic is the antisense oligonucleotide. These oligomers are predominantly used to inhibit mRNA expression. For cancer chemotherapy, the Bcl-2 antisense oligonucleotide is currently in phase III clinical trials. Transcription factor decoys form DNA:protein heteroduplexes and produce cellular responses at the genomic rather than transcriptional level. The use of other transcription factor decoys as oncologic reagents is now being developed. The phenomenon of RNA interference has only recently been discovered to occur in plants as a response to viral infection. Small interfering RNAs cause mRNA inhibition. siRNAs also inhibit expression of mRNA, however the intracellular cascade is quite different. siRNA could prove to be more powerful and longer lasting than antisense. Several DNA therapeutics are currently being studied. This review will focus on antisense oligonucleotides, transcription factor decoys and siRNA with an emphasis on how they can be employed as anticancer agents. Mechanism of action and design strategies will be summarized, as well as therapeutic targets and demonstrated clinical efficacy for each reagent.
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PMID:Oligonucleotides as anticancer agents: from the benchside to the clinic and beyond. 1610 40

CD8(+) T cells are activated by the presentation of antigenic peptide through MHC class I molecules. Newly synthesized proteins formed as defective ribosomal products (DRiPs) can act as a major source of antigenic peptides for MHC class I presentation pathway. Majority of these peptides are generated from the intracellular degradation of self antigens. In the present study, we have shown that newly synthesized T cell receptor (TCR) beta chains formed as DRiPs in T cells are ubiquitinated and degraded by the proteasomes. These TCR-DRiPs are processed and presented by activated T cells to cognate anti-idiotypic CD8(+) T cells. Presentation of TCR idiopeptide (peptide derived from the variable region of idiotypic TCR) by activated T cells leads to Bcl-2 expression and cytokine secretion by anti-idiotypic CD8(+) T cells. Presentation of intracellular antigen by T cells may have important implications in immunoregulation, control of lymphotropic virus infection and autoimmune diseases.
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PMID:Idiotypic T cells specific for Morbillivirus nucleocapsid protein process and present their TCR to cognate anti-idiotypic CD8+ T cells. 1618 24

Antiapoptotic Bcl-2 family proteins inhibit apoptosis in cultured cells by binding BH3 domains of proapoptotic Bcl-2 family members via a hydrophobic BH3 binding groove on the protein surface. We investigated the physiological importance of the BH3 binding groove of an antiapoptotic Bcl-2 protein in mammals in vivo by analyzing a viral Bcl-2 family protein. We show that the gamma-herpesvirus 68 (gammaHV68) Bcl-2 family protein (gammaHV68 v-Bcl-2), which is known to inhibit apoptosis in cultured cells, inhibits both apoptosis in primary lymphocytes and Bax toxicity in yeast. Nuclear magnetic resonance determination of the gammaHV68 v-Bcl-2 structure revealed a BH3 binding groove that binds BH3 domain peptides from proapoptotic Bcl-2 family members Bax and Bak via a molecular mechanism shared with host Bcl-2 family proteins, involving a conserved arginine in the BH3 peptide binding groove. Mutations of this conserved arginine and two adjacent amino acids to alanine (SGR to AAA) within the BH3 binding groove resulted in a properly folded protein that lacked the capacity of the wild-type gammaHV68 v-Bcl-2 to bind Bax BH3 peptide and to block Bax toxicity in yeast. We tested the physiological importance of this v-Bcl-2 domain during viral infection by engineering viral mutants encoding a v-Bcl-2 containing the SGR to AAA mutation. This mutation resulted in a virus defective for both efficient reactivation of gammaHV68 from latency and efficient persistent gammaHV68 replication. These studies demonstrate an essential functional role for amino acids in the BH3 peptide binding groove of a viral Bcl-2 family member during chronic infection.
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PMID:A surface groove essential for viral Bcl-2 function during chronic infection in vivo. 1620 Oct 11


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