Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenovirus type 5 encodes a 14.7-kDa protein that protects infected cells from tumor necrosis factor-induced cytolysis by an unknown mechanism. In this report, we demonstrate that infection of cells with an adenovirus vector expressing Fas ligand induced rapid apoptosis that was blocked by coinfection with a virus expressing 14. 7K. Moreover, AdFasL/G infection resulted in the rapid activation of DEVD-specific caspases, and caspase activation was blocked by coinfection with Ad14.7/G. Cell death induced by the overexpression of Fas ligand, Fas-associated death domain-containing protein (FADD)/MORT1, or FADD-like interleukin-1beta-converting enzyme (FLICE)/caspase-8 in a virus-free system was efficiently blocked by 14.7K expression. Moreover, we demonstrate that 14.7K interacts with FLICE. These results support the idea that FLICE is a cellular target for the 14.7-kDa protein.
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PMID:Interaction of the adenovirus 14.7-kDa protein with FLICE inhibits Fas ligand-induced apoptosis. 948 17

Adenovirus vectors transduce liver hepatocytes with extreme efficiency; however, transgene expression is eliminated within 2 weeks. Extinction of transgene expression has been attributed to infiltrating cytotoxic T lymphocytes (CTLs) in the liver in a process that resembles a number of human diseases, including viral and autoimmune hepatitis. In this study we investigated the role of Fas-Fas ligand interactions in killing of vector-transduced hepatocytes in vitro and in vivo. Intrahepatic lymphocytes (IHLs) isolated from livers of mice administered adenovirus vector demonstrated cytolytic activity against vector-infected primary hepatocytes. The in vitro CTL activity of the IHLs involving both CD4+ and CD8+ T cells was MHC class I restricted and could be blocked by soluble Fas-IgG. Adoptive transfer of IHLs from immune-competent mice immunized with Ad-lacZ into Ragl-deficient mice previously infused with Ad-lacZ resulted in rapid elimination of beta-galactosidase-transduced hepatocytes. Transfer of these cells into Fas-deficient mice (B6-lpr) failed to eliminate lacZ expression; likewise IHLs from immunized FasL-deficient mice (B6-gld) failed to eliminate lacZ expression in Rag1-deficient mice. Finally, in vivo administration of soluble Fas-IgG abrogated the ability of Ad-lacZ-primed IHLs to eliminate transgene expression. These studies establish an essential role for Fas-Fas ligand interactions in the mechanism of elimination of adenoviral vector-mediated transgene expression in the liver.
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PMID:Fas-Fas ligand interactions play a major role in effector functions of cytotoxic T lymphocytes after adenovirus vector-mediated gene transfer. 1002 50

Adenovirus vectors expressing gene products that can induce apoptosis have potential utility in gene therapy applications ranging from the treatment of proliferative diseases to transplantation. However, adenovirus vectors carrying proapoptotic gene products are difficult to produce, as the apoptotic environment is not conducive to adenovirus gene expression and replication. Production of AdFasL/G, an adenovirus vector that expresses high levels of Fas ligand, was severely reduced in the 293 packaging cell line. Increased yields of AdFasL/G were achieved by inclusion of peptide-based caspase inhibitors in the growth medium. However, use of these inhibitors for large-scale production would be difficult and expensive. A screen for gene products that increase the yield of AdFasL/G in 293 cells revealed that the poxvirus serpin CrmA and the adenovirus 14.7K product were able to increase virus yields significantly. Apoptosis induced by AdFasL/G was attenuated in 293CrmA cell lines and virus titers were increased dramatically. However, serial passage of AdFasL/G on 293CrmA cells resulted in the generation of replication-competent adenovirus. To resolve this problem, the CrmA gene was introduced into AE25 cells, an E1-complementing cell line that has limited sequence identity with the vectors. AdFasL/G titers were increased 100-fold on AE25CrmA cells relative to the AE25 cells and RCA contamination was not detectable. In addition, adenovirus vectors that express FADD, caspase 8, and Fas/APO1 were produced efficiently in AE25CrmA and 293CrmA.
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PMID:Improved production of adenovirus vectors expressing apoptotic transgenes. 1064 46

Adenovirus-mediated gene transfer of Fas ligand (FasL) inhibits neointimal formation in balloon-injured rat carotid arteries. Vascular smooth muscle (VSM) cells coexpressing murine FasL and p35, a baculovirus gene that inhibits caspase activity, are not susceptible to FasL-mediated apoptosis in vitro but are capable of inducing apoptosis of VSM cells that do not express p35. We reasoned that coexpression of p35 in FasL-transduced VSM cells in vivo would promote their survival, enhance FasL-induced apoptosis of adjacent VSM cells, and thereby facilitate a greater inhibition of neointimal formation. In balloon-injured rabbit femoral arteries, either Ad2/FasL/p35 or Ad2/FasL was infused into the injured site and withdrawn 20 min later. Both vectors induced a dose-dependent reduction (p < 0.05) of the neointima-to-media ratio when assessed 14 days later. However, Ad2/FasL/p35 exhibited a significantly greater inhibition of neointimal formation than Ad2/FasL. In a more clinically relevant model of restenosis, rabbit iliac arteries were injured with an angioplasty catheter under fluoroscopic guidance. Adenoviral vectors were delivered locally to the injured site over a period of 2 min, using a porous infusion balloon catheter. Twenty-eight days after gene transfer angiographic and histologic assessments indicated a significant (p < 0.05) inhibition of iliac artery lumen stenosis and neointimal formation by Ad2/FasL/p35 (5 x 10(11) particles per artery). The extent of inhibition was comparable to that achieved with Ad2/TK, an adenoviral vector encoding thymidine kinase (5 x 10(11) particles per artery) and coadministration of ganciclovir for 7 days. These data suggest that coexpression of p35 in FasL-transduced VSM cells is more potent at inhibiting neointimal formation and as such represents an improved gene therapy approach for restenosis.
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PMID:Enhancement of Fas ligand-induced inhibition of neointimal formation in rabbit femoral and iliac arteries by coexpression of p35. 1177 3

Adenovirus type 5 E1A protein (E1A) associates with anti-tumor activities by reversing the transformed phenotype, inhibiting metastasis, and inducing apoptosis. We have previously identified that E1A suppresses the expression of Axl, a transforming tyrosine kinase and that Axl-Gas6 receptor-ligand interaction prevents E1A transfectants from apoptosis induced by serum deprivation. To determine how the Axl-Gas6 interaction prevents E1A-mediated apoptosis, we analysed the expression of anti-apoptotic molecules and found that the activated form of Akt was suppressed in the E1A transfectant ip 1-E1A and that Gas6 was able to activate Akt in ip 1-E1A cells reexpressing Axl (ip 1-E1A-Axl). To determine whether activated Akt is required to prevent E1A-mediated apoptosis, ip 1-E1A-Axl cells were treated with the phosphatidylinositol-3'-OH kinase inhibitor wortmannin or transfected with a dominant negative Akt mutant. In both cases, Gas6 no longer protected the cells from serum deprivation-induced apoptosis. Thus, we conclude that activated Akt is required for Axl-Gas6 signaling to prevent E1A-mediated apoptosis induced by serum deprivation. Downstream molecules of Akt, including NF-kappaB, Fas ligand, and BAD were examined, among which phosphorylation of BAD by Axl-Gas6 signaling is associated with the anti-apoptotic activity of Akt in our study.
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PMID:Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis. 1182 45

Multiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis. We investigated the mechanism of p53-induced apoptosis using primary cultures of central nervous system-derived adult human oligodendrocytes. Adenovirus-mediated p53 overexpression resulted in up-regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase-mediated apoptosis of the oligodendrocytes. The oligodendrocytes were protected from p53-induced cell death by blocking signaling through Fas and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.
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PMID:Oligodendrocyte injury in multiple sclerosis: a role for p53. 1269 89

Hepatocellular carcinoma (HCC) has been reported to be resistant to Fas-mediated apoptosis. In present study, experiments were conducted to investigate the potential effects of CYP2E1 overexpression on susceptibility of HCC to Fas-mediated cytotoxicity. HCC cell line HepG2 was infected with Ad-CYP2E1 to enhance the expression of CYP2E1, followed by treatment with low toxic dose of recombinant human Fas ligand (FasL, 0.5 ng/ml) in the presence of Actinomycin D (Act D, 125 ng/ml). High level of Fas expression was found in HepG2 cells. Its protein level and distribution kept unchanged after different treatments. Compared with control, CYP2E1 expressed HepG2 cells were more sensitive to FasL plus Act D. The sensitivity was elevated in a multiplicity of infection (m.o.i)-dependent manner, which was dramatically suppressed by CYP2E1 inhibitor diallyl disulfide (DAS) (p < 0.01). The percentage of apoptotic cells caused by FasL/Act D was increased from 18.7 to 75% after infection with Ad-CYP2E1 (p < 0.01). DAS treatment resulted in 60% reduction of apoptotic ratio (p < 0.01). Antioxidants GSH ethyl ester, Vitamin C and Vitamin E efficiently protected against cytotoxicity induced by FasL plus Act D in CYP2E1-expressed HepG2 cells. After adding FasL/Act D, increased caspases activities, lipid preoxidation and reduced GSH level, as well as mitochondrial release of cytochrome c were found in Ad-CYP2E1 infected cells (all p < 0.01); these changes were significantly attenuated by DAS (all p < 0.05). These results suggested that CYP2E1 potentiates Fas-mediated HepG2 cells toxicity via the induction of oxidative stress to promote apoptosis. Adenovirus-mediated overexpresson of CYP2E1 may have an important role in the elimination of hepatoma cells mediated by immune effector cells in the liver.
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PMID:Overexpression of CYP2E1 enhances sensitivity of hepG2 cells to fas-mediated cytotoxicity. 1849 73