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 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 E4orf4 protein has been shown to induce transformed cell-specific, protein phosphatase 2A-dependent, and p53-independent apoptosis. It has been further reported that the E4orf4 apoptotic pathway is caspase-independent in CHO cells. Here, we show that E4orf4 induces caspase activation in the human cell lines H1299 and 293T. Caspase activation is required for apoptosis in 293T cells, but not in H1299 cells. Dominant negative mutants of caspase-8 and the death receptor adapter protein FADD/MORT1 inhibit E4orf4-induced apoptosis in 293T cells, suggesting that E4orf4 activates the death receptor pathway. Cytochrome c is released into the cytosol in E4orf4-expressing cells, but caspase-9 is not required for induction of apoptosis. Furthermore, E4orf4 induces accumulation of reactive oxygen species (ROS) in a caspase-8- and FADD/MORT1-dependent manner, and inhibition of ROS generation by 4,5-dihydroxy-1, 3-benzene-disulfonic acid (Tiron) inhibits E4orf4-induced apoptosis. Thus, our results demonstrate that E4orf4 engages the death receptor pathway to generate at least part of the molecular events required for E4orf4-induced apoptosis.
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PMID:Caspase activation by adenovirus e4orf4 protein is cell line specific and Is mediated by the death receptor pathway. 1113 92

Bcl-2 is a member of the large Bcl-2 family and protects cells from apoptosis. Ultraviolet B (UVB) irradiation induces apoptosis of keratinocytes that is known as "sunburn cells." Previously we reported that UVB irradiation induces apoptosis accompanied by sequential activation of caspase 8, 3 and 1 in keratinocytes, and that the process is inhibited by various caspase inhibitors. Using bcl-2-expressing adenovirus vector we investigated the effect of Bcl-2 on UVB-induced apoptosis. Adenovirus vector efficiently introduced bcl-2 gene in cultured normal mouse keratinocytes (NMK cells); almost all NMK cells (1 x 10(6)) were transfected at 1 x 10(8) plaque-forming unit (PFU)/mL. Bcl-2-transfected NMK cells were significantly resistant to UVB-induced apoptosis with the suppressive effect dependent on the Bcl-2 expression level. Following UVB irradiation caspase 8, 3 and 9 activities were stimulated in NMK cells, whereas in bcl-2-transfected cells only caspase 8, but not caspase 3 or 9, activity was stimulated. In order to investigate the effect of Bcl-2 in vivo topical application of Ad-bcl-2 on tape-stripped mouse skin was performed. Following the application Bcl-2 was efficiently overexpressed in almost all viable keratinocytes. The expression was transient with the maximal expression of Bcl-2 on the first day following the application of 1 x 10(9) PFU in 200 microL. The introduced Bcl-2 remained at least for 6 days. UVB irradiation (1250 J/m2) induced apoptosis within 12 h and the maximal effect was observed at 24 h in control mouse skin. Both bcl-2-transfected and topical caspase 3 inhibitor-treated mice skin were resistant to UVB-induced apoptosis. The suppressive effect of Bcl-2 was more potent than that of caspase 3 inhibitor application. Topical application of empty adenovirus vector alone had no effect on Bcl-2 expression or UVB-induced apoptosis. These results indicate that adenovirus vector is an efficient gene delivery system into keratinocytes and that Bcl-2 is a potent inhibitor of UVB-induced apoptosis both in vitro and in vivo.
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PMID:In vitro and in vivo transfer of bcl-2 gene into keratinocytes suppresses UVB-induced apoptosis. 1168 38

The PTEN tumor suppressor is frequently mutated in human tumors. Loss of PTEN function is associated with constitutive survival signaling through the phosphatidylinositol-3 kinase/Akt pathway. Therefore, we asked if reconstitution of PTEN function would lead to the reversal of resistance to apoptosis in prostate cancer cells. Adenovirus-mediated expression of PTEN completely suppressed constitutive Akt activation in LNCaP prostate cancer cells and enhanced apoptosis induced by a broad range of apoptotic stimuli. PTEN expression sensitized cells to death receptor-mediated apoptosis induced by tumor necrosis factor, anti-Fas antibody, and TRAIL. PTEN also sensitized cells to non-receptor mediated apoptosis induced by a kinase inhibitor staurosporine and chemotherapeutic agents mitoxantrone and etoposide. PTEN-mediated apoptosis was accompanied by caspase-3 and caspase-8 activation and was inhibited by a broad specificity caspase inhibitor Z-VAD-fmk. Bcl-2 overexpression also blocked PTEN-mediated apoptosis. Lipid phosphatase activity of PTEN is required for apoptosis as the PTEN G129E mutant selectively deficient in lipid phosphatase activity was unable to sensitize cells to apoptosis. PTEN-mediated apoptosis involves a FADD-dependent pathway for both death receptor-mediated and drug-induced apoptosis as coexpression of a dominant negative FADD mutant blocked PTEN-mediated apoptosis. Since in death receptor signaling, FADD mediates activation of caspase-8, which in turn cleaves BID, and since caspase-8 is activated in PTEN-mediated apoptosis, we examined BID cleavage in PTEN-mediated apoptosis. PTEN facilitated BID cleavage after treatment with low doses of staurosporine and mitoxantrone. BID cleavage was inhibited by dominant negative FADD. Taken together, these data are consistent with the hypothesis that PTEN promotes drug-induced apoptosis by facilitating caspase-8 activation and BID cleavage through a FADD-dependent pathway.
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PMID:PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway. 1180 75

Tumor necrosis factor alpha (TNF-alpha) activates both apoptosis and NF-kappaB-dependent survival pathways, the former of which requires inhibition of gene expression to be manifested. c-FLIP is a TNF-alpha-induced gene that inhibits caspase-8 activation during TNF-alpha signaling. Adenovirus infection and E1A expression sensitize cells to TNF-alpha by allowing apoptosis in the absence of inhibitors of gene expression, suggesting that it may be disabling a survival signaling pathway. E1A promoted TNF-alpha-mediated activation of caspase-8, suggesting that sensitivity was occurring at the level of the death-inducing signaling complex. Furthermore, E1A expression downregulated c-FLIP(S) expression and prevented its induction by TNF-alpha. c-FLIP(S) and viral FLIP expression rescued E1A-mediated sensitization to TNF-alpha by restoring the resistance of caspase-8 to activation, thereby preventing cell death. E1A inhibited TNF-alpha-dependent induction of c-FLIP(S) mRNA and stimulated ubiquitination- and proteasome-dependent degradation of c-FLIP(S) protein. Since elevated c-FLIP levels confer resistance to apoptosis and promote tumorigenicity, interference with its induction by NF-kappaB and stimulation of its destruction in the proteasome may provide novel therapeutic approaches for facilitating the elimination of apoptosis-refractory tumor cells.
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PMID:E1A sensitizes cells to tumor necrosis factor alpha by downregulating c-FLIP S. 1255 4

Tissue inhibitors of metalloproteinases (TIMPs) are important regulators of matrix metalloproteinase (MMP) and adamalysin (ADAM) activity. We have previously shown that adenovirally expressed tissue inhibitor of metalloproteinases-3 (TIMP-3) induces apoptosis in melanoma cells and inhibits growth of human melanoma xenografts. Here, we have studied the role of death receptors in apoptosis of melanoma cells induced by TIMP-3. Our results show, that the exposure of three metastatic melanoma cell lines (A2058, SK-Mel-5, and WM-266-4) to recombinant TIMP-3, N-terminal MMP inhibitory domain of TIMP-3, as well as to adenovirally expressed TIMP-3 results in stabilization of tumor necrosis factor receptor-1 (TNF-RI), FAS, and TNF-related apoptosis inducing ligand receptor-1 (TRAIL-RI) on melanoma cell surface and sensitizes these cells to apoptosis induced by TNF-alpha, anti-Fas-antibody and TRAIL. Stabilization of death receptors by TIMP-3 results in activation of caspase-8 and caspase-3, and subsequent apoptosis is blocked by specific caspase-8 inhibitor (Z-IETD-FMK) and by pan-caspase inhibitor (Z-DEVD-FMK). Adenovirus-mediated expression of TIMP-3 in human melanoma xenografts in vivo resulted in increased immunostaining for TNF-RI, FAS, and cleaved caspase-3, and in apoptosis of melanoma cells. Taken together, these results show that TIMP-3 promotes apoptosis in melanoma cells through stabilization of three distinct death receptors and activation of their apoptotic signaling cascade through caspase-8.
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PMID:Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. 1268 14

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. However, the underlying mechanism of endothelial cell injury in hyperhomocysteinemia has not been elucidated. In this study, we examined the effect of homocysteine (Hcy) on Fas-mediated apoptosis in endothelial cells. Hcy-induced upregulation of Fas in endothelial cells (ECs) in a dose-dependent manner. At the same time, Hcy increased intracellular peroxide in ECs. Hcy-induced Fas expression was inhibited by the treatment with catalase. Hcy increased NF-kappaB DNA binding activity, and adenovirus-mediated transfection of a Ikappa-B mutant (Ikappa-B mt) gene inhibited Hcy-induced Fas expression. ECs were sensitive to Fas-mediated apoptosis when exposed to Hcy. Under these condition, Ikappa-B mt protected ECs from Fas-mediated apoptosis. In addition, Hcy inhibited expression of the caspase-8 inhibitor FLICE-inhibitory protein (FLIP). Adenovirus-mediated transfection of constitutively active Akt gene abolished the Hcy-mediated downregulation of FLIP. These data suggest that upregulation of Fas expression and downregulation of FLIP is a mechanism through which Hcy induces EC apoptosis.
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PMID:Homocysteine enhances endothelial apoptosis via upregulation of Fas-mediated pathways. 1509 73

Adenovirus-mediated mda-7 (Ad-mda7) gene transfer has been shown to induce apoptosis in various human cancer cells while sparing normal cells. Vitamin E succinate (VES) is also known to exhibit antitumor activity against a number of human cancer cell lines. We hypothesized that a combination of the two agents would produce an enhanced antitumor effect in MDAH2774 human ovarian cancer cells. Treatment of MDAH2774 cells with Ad-mda7 plus VES resulted in enhanced antitumor activity that involved the activation of two apoptotic pathways. Activation of the extrinsic pathway was demonstrated by increased cell-surface Fas expression and cleavage of Bid and caspase-8. Activation of the intrinsic pathway was demonstrated by disruption of mitochondrial potential; and activation of downstream capase-9 and caspase-3 via cytochrome C release. In contrast, the combination of Ad-mda7 plus VES did not show any antitumor activity against normal fibroblasts, indicating selective tumor cell killing. Our in vitro results provide a basis for further preclinical testing of Ad-mda7 plus VES as a potential cancer treatment strategy.
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PMID:Vitamin E succinate in combination with mda-7 results in enhanced human ovarian tumor cell killing through modulation of extrinsic and intrinsic apoptotic pathways. 1744 72

We have previously reported that the downregulation of MMP-2 by adenovirus-mediated delivery of MMP-2 siRNA (Ad-MMP-2) reduced spheroid invasion and angiogenesis in vitro, and, metastasis and tumor growth in vivo. In this study, we investigated the mechanism of Ad-MMP-2-mediated growth inhibition in vitro and in vivo. Ad-MMP-2 infection led to the induction of apoptosis as determined by TUNEL assay, Annexin-V staining and PARP-1 cleavage in a dose-dependent manner in A549 cells. Ad-MMP-2 decreased the content of the antiapoptotic members of the Bcl-2 family proteins (Bcl-2 and Bcl-xL) and increased the content of the pro-apoptotic members of the Bcl-2 family (Bax and Bcl-xS) as determined by immunoblotting analysis. Furthermore, Ad-MMP-2-mediated apoptosis was accompanied by increase in truncated Bid, release of cytochrome c and the activation of caspase-8, -9 and -3. Immunoblot analysis showed that Ad-MMP-2 infection caused upregulation of Fas/Fas-L and FADD, and Anti-Fas-L antibody reversed Ad-MMP-2-induced apoptosis. Tissue inhibitor of metalloproteinases (TIMP)-3, an endogenous inhibitor of MMP-2, which cleaves Fas-L and activates the Fas/Fas-L inducing apoptotic pathway, was increased in Ad-MMP-2-treated cells. Adenovirus-mediated expression of MMP-2 siRNA in human lung xenografts in vivo resulted in increased immunostaining of Fas, Fas-L, cleaved Bid and TIMP-3. This is the first report, to our knowledge, showing that MMP-2 inhibition upregulates TIMP-3 levels, which in turn, promotes apoptosis in lung cancer.
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PMID:MMP-2 siRNA induced Fas/CD95-mediated extrinsic II apoptotic pathway in the A549 lung adenocarcinoma cell line. 1759 56


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