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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromosomal fragile sites are regions that are intrinsically unstable and are susceptible to experimentally induced damage. In most cases, the target and mechanism of induction of fragility are unknown. Using ectopic integration of engineered DNA arrays to create "new" fragile sites, we and others have previously shown that the transcriptionally competent U2 gene is necessary and sufficient for induction of fragility at the RNU2 locus upon infection of human cells with Adenovirus 12. In the present study we have investigated the response of the RNU2 locus to cytosine arabinoside (araC), an inhibitor of DNA polymerases and a common inducer of fragile sites. We demonstrate that the RNU2 locus is sensitive to the drug and that araC-induced fragility is dependent upon a functional U2 gene and on the expression of the cellular p53 protein. Our results identify a novel DNA structure associated with fragile sites and suggest a role for transcription and repair processes in RNU2 fragility.
Somat Cell Mol Genet 1997 Nov
PMID:Induction of fragility at the human RNU2 locus by cytosine arabinoside is dependent upon a transcriptionally competent U2 small nuclear RNA gene and the expression of p53. 966 1

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by granuloma formation. We recently showed that interferon-gamma (IFN-gamma) is essential for inflammation and granuloma formation in HP. Interleukin-10 (IL-10) counteracts many of the biologic effects of IFN-gamma, suggesting that IL-10 modulates inflammation and granuloma formation in HP. We compared the expression of HP in C57BL/6 mice that lack IL-10 (IL-10 knockout [KO]) with that in wild-type (WT) littermates. IL-10 KO and WT mice were exposed to the thermophilic bacteria Saccharopolyspora rectivirgula or to saline alone for 3 wk. The IL-10 KO mice had higher cell counts in their bronchoalveolar lavage fluid (2.85 +/- 0. 43 x 10(6)) than did WT mice (1.4 +/- 0.3 x 10(6)/ml; P < 0.03), with a more prominent neutrophil response. They also had greater inflammation after antigen exposure than did the WT mice (P < 0. 0001). There was increased upregulation of IFN-gamma, IL-1, and tumor necrosis factor-alpha (TNF-alpha) mRNAs in the lungs of IL-10 KO mice. Adenovirus-mediated gene transfer of IL-10 to the liver of IL-10 KO mice reduced the inflammation from that seen in WT mice. These studies show that IL-10 has important anti-inflammatory properties in HP, and that lack of this cytokine leads to a more severe granulomatous inflammatory response.
Am J Respir Cell Mol Biol 1998 Nov
PMID:Interleukin-10 modulates the severity of hypersensitivity pneumonitis in mice. 980 46

Adenovirus has attracted much attention as a vector for gene therapy. Integrin alphavbeta3 and alphavbeta5 mediate adenovirus internalization into cells. We examined adenoviral transduction efficiency and expression of integrin alphavbeta3 alphavbeta5 in 9 human gastric carcinoma cell lines. The percentage of -gal-positive cells was more than 85% 3 days after infection with recombinant adenovirus carrying the bacterial LacZ gene (AxCALacZ) at a dose of 25 MOI in 7 cell lines and the transduction efficiency was 32 and 42% in HSC-39 and MKN-28 cells, respectively. Adenoviral transduction efficiency did not correlate with the histological cell types. Flow cytometric analysis revealed relatively high expression of integrin alphavbeta5 in MKN-28 and OCUM-2M cells, followed by MKN-1, MKN-7, MKN-45, MKN-74, TMK-1 and KATO-III cells. HSC-39 cells minimally expressed integrin alphavbeta5. On the other hand, integrin alphavbeta3 was expressed only in MKN-1 cells. These results suggest that the adenovirus vector might be useful for gene transduction into human gastric carcinoma cells and the transduction efficiency partly correlates with the expression levels of integrin alphavbeta5 but not integrin alphavbeta3.
Int J Mol Med 1998 Jul
PMID:Adenoviral transduction efficiency partly correlates with expression levels of integrin alphavbeta5, but not alphavbeta3 in human gastric carcinoma cells. 985 44

Current therapy for glioma is suboptimal. The transfer of apoptosis genes to tumors constitutes one of the most promising strategies for cancer gene therapy. We have previously shown that massive apoptosis occurs when wild-type p53 or E2F-1 expression is induced in glioma. However, the mechanism of action and the efficiency in inducing apoptosis of these two proteins are not similar. Adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain wild-type p53 genotype or overexpress the p21 protein. The p16/Rb/E2F pathway is the most frequent target of genetic alterations in gliomas, and therefore constitutes a suitable target for gene therapy strategies. However, the transfer of either the p16 or Rb gene to glioma cells results in cytostatic effect. The E2F-1 protein is able to induce generalized apoptosis in gliomas independently of the p53, p16 or Rb status. In addition, p21- or p16-mediated growth arrest did not protect glioma cells from E2F-1-mediated apoptosis. The apoptotic molecule bax is induced in p53-mediated apoptosis, but bax is not induced in E2F-1-mediated apoptosis in glioma cells. Careful selection of patients may be necessary before designing therapeutic strategies using either p53 or E2F-1 as a therapeutic tools for glioma patients.
Int J Mol Med 1999 Jan
PMID:Gene therapy for gliomas: p53 and E2F-1 proteins and the target of apoptosis. 986 90

Increased generation of reactive oxygen species (ROS) and low levels of antioxidants may cause morbidity in premature infants on supplemental oxygen. Glutathione (GSH)-dependent antioxidant systems protect against ROS, and regenerating GSH from GSH disulfide (GSSG) by the flavoenzyme GSH reductase (GR) is essential for the optimal function of this system. Previously, we have observed enhanced resistance to t-butyl hydroperoxide (t-BuOOH) in Chinese hamster ovary cells stably transfected with a vector (leader sequence GR [LGR]) for human GR cDNA that contained a functional synthetic mitochondrial targeting signal. The present studies were designed to investigate adenovirus-mediated gene transfer of LGR to H441 cells and resistance of such cells to t-BuOOH. Adenovirus-mediated transfection of H441 cells with LGR increased total GR activities more than 11-fold (mitochondria more than 10-fold and cytosolic more than 7-fold) and protected against t-BuOOH cytotoxicity, as indicated by lower fractional release of cellular lactate dehydrogenase (LDH) than was observed in wild-type untransfected cells (CON) or in cells transfected with a control gene (human manganese superoxide dismutase in the antisense orientation [DOS]) (*LGR 6.6 +/- 1.7; DOS 16 +/- 1.8; CON 16.6 +/- 0.7% LDH release). In addition, cells transfected with LGR retained higher GSH/GSSG ratios (*LGR 66 +/- 0.4; DOS 47 +/- 1; CON 52.6 +/- 2.3) and released less GSH + GSSG to the media in response to challenge with t-BuOOH (*LGR 0.05 +/- 0.01; DOS 0.08 +/- 0.01; CON 0.07 +/- 0.01 nmol/mg of protein) than did wild-type cells or cells transfected with a control vector, indicating an enhanced ability of the LGR cells to reduce GSSG formed in response to exposure to t-BuOOH. In conclusion, adenovirus-mediated gene transfer of LGR enhanced cellular GR activities and protected H441 cells from oxidant stresses.
Am J Respir Cell Mol Biol 1999 Feb
PMID:Gene transfer of mitochondrially targeted glutathione reductase protects H441 cells from t-butyl hydroperoxide-induced oxidant stresses. 992 16

Human tracheal gland serous (HTGS) cells are now considered one principal pulmonary target for the gene therapy of cystic fibrosis (CF). We developed a CF tracheal gland serous cell line, CF-KM4, obtained by the transformation of primary cultures of CF tracheal gland serous cells homozygous for the DeltaF508 mutation by using the wild-type SV40 virus. This cell line retained epithelial and secretory features of the native CF-HTGS cells in primary culture, namely, presence of cytokeratin, constitutive secretion of secretory leukocyte proteinase inhibitor, absence of responsiveness to carbachol and isoproterenol, and defective cyclic adenosine monophosphate-dependent chloride channel activity. Adenovirus-mediated CF transmembrane conductance regulator (CFTR) gene transfer into CF-KM4 cells corrected the defective chloride channel activity as well as the responsiveness to adrenergic and cholinergic agonists. In contrast, control transfection using adenovirus-mediated beta-galactosidase gene transfer was totally ineffective. In conclusion, these results present a stable CF tracheal gland cell line that has retained its epithelial and CF-specific defective secretory characteristics which are corrected after CFTR gene transfer. This cell line therefore appears to be a useful tool for large-scale molecular and cellular pharmacologic investigations designed to test potential therapies of the disease CF.
Am J Respir Cell Mol Biol 1999 Apr
PMID:A cystic fibrosis tracheal gland cell line, CF-KM4. Correction by adenovirus-mediated CFTR gene transfer. 1010 Oct

Adenovirus E1B 55,000-molecular-weight protein (55K) binds to host cell p53, stabilizing it, greatly increasing its affinity for its cognate DNA-binding site, and converting it from a regulated activator to a constitutive repressor. Here we analyzed the mechanism of repression by the p53-E1B 55K complex. E1B 55K repression requires that 55K be tethered to the promoter by binding directly to DNA-bound p53. Transcription from an assembled, p53-activated preinitiation complex was not repressed by the subsequent addition of E1B 55K, suggesting that either sites of 55K interaction with p53 or targets of 55K in the preinitiation complex are blocked. Specific E1B 55K repression was observed in reactions lacking TFIIA and with recombinant TATA-binding protein in place of TFIID, conditions under which p53 does not activate transcription. Thus, E1B 55K does not simply inhibit a p53-specific activation mechanism but rather blocks basal transcription. As a consequence, E1B 55K may repress transcription from any promoter with an associated p53-binding site, no matter what other activators associate with the promoter. E1B 55K did not repress basal transcription in reactions with recombinant and highly purified general transcription factors and RNA polymerase II but rather required a corepressor that copurifies with the polymerase.
Mol Cell Biol 1999 May
PMID:Corepressor required for adenovirus E1B 55,000-molecular-weight protein repression of basal transcription. 1020 64

During myogenesis, proliferating myoblasts withdraw from the cell cycle, acquire an apoptosis-resistant phenotype, and differentiate into myotubes. Previous studies indicate that myogenic induction of the cyclin-dependent kinase inhibitor p21 results in an inhibition of apoptotic cell death in addition to its role as a negative cell cycle regulator. Here we demonstrate that the protein encoded by the Akt proto-oncogene is induced in C2C12 cells during myogenic differentiation with a corresponding increase in kinase activity. In differentiating cultures, expression of dominant-negative forms of Akt increase the frequency of cell death whereas expression of wild-type Akt protects against death, indicating that Akt is a positive modulator of myocyte survival. Antisense oligonucleotides against p21 block cell cycle withdrawal, inhibit Akt induction, and enhance cell death in differentiating myocyte cultures. Adenovirus-mediated transfer of wild-type or constitutively active Akt constructs confer partial resistance to cell death under conditions where cell cycle exit is blocked by the antisense oligonucleotides. Collectively, these data indicate that cell cycle withdrawal facilitates the induction of Akt during myogenesis, promoting myocyte survival.
Mol Cell Biol 1999 Jul
PMID:Cell cycle withdrawal promotes myogenic induction of Akt, a positive modulator of myocyte survival. 1037 56

Insulin receptor substrate-1 (IRS-1) is a major substrate of the insulin receptor and acts as a docking protein for Src homology 2 domain containing signaling molecules that mediate many of the pleiotropic actions of insulin. Insulin stimulation elicits serine/threonine phosphorylation of IRS-1, which produces a mobility shift on SDS-PAGE, followed by degradation of IRS-1 after prolonged stimulation. We investigated the molecular mechanisms and the functional consequences of these phenomena in 3T3-L1 adipocytes. PI 3-kinase inhibitors or rapamycin, but not the MEK inhibitor, blocked both the insulin-induced electrophoretic mobility shift and degradation of IRS-1. Adenovirus-mediated expression of a membrane-targeted form of the p110 subunit of phosphatidylinositol (PI) 3-kinase (p110CAAX) induced a mobility shift and degradation of IRS-1, both of which were inhibited by rapamycin. Lactacystin, a specific proteasome inhibitor, inhibited insulin-induced degradation of IRS-1 without any effect on its electrophoretic mobility. Inhibition of the mobility shift did not significantly affect tyrosine phosphorylation of IRS-1 or downstream insulin signaling. In contrast, blockade of IRS-1 degradation resulted in sustained activation of Akt, p70 S6 kinase, and mitogen-activated protein (MAP) kinase during prolonged insulin treatment. These results indicate that insulin-induced serine/threonine phosphorylation and degradation of IRS-1 are mediated by a rapamycin-sensitive pathway, which is downstream of PI 3-kinase and independent of ras/MAP kinase. The pathway leads to degradation of IRS-1 by the proteasome, which plays a major role in down-regulation of certain insulin actions during prolonged stimulation.
Mol Endocrinol 2000 Jun
PMID:A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. 1084 81

Adenovirus-mediated gene transfer may hold much promise in the treatment of human cancer. However, concerns regarding vector dissemination beyond the target tissue, particularly with replication-competent viruses, require an evaluation of the persistence of viral infection in collateral tissue and vector-associated toxicities. In addition, for indications such as prostate cancer, the proximity of the point of viral administration to organs of the male reproductive system raises concerns regarding inadvertent germ-line transmission of genes carried by the virus. To address these concerns, the biodistribution, persistence, toxicity, and potential of germ-line transmission of a replication-competent adenovirus (Ad5-CD/TKrep) following intraprostatic administration in the mouse was examined. Ad5-CD/TKrep (10(10) vp, 5 x 10(11) vp/kg) was injected intraprostatically on Day 1 of the study and its presence in the major organs of the male urogenital tract (prostate, testes, seminal vesicles, and urinary bladder) and liver was determined on Days 8 and 29. For comparison, a parallel group of animals was injected with the same dose of a related replication-defective Ad5-FGNR virus. To evaluate germ-line transmission, Ad5-CD/TKrep-injected males were mated to females on Days 8 and 29 and resulting embryos were examined for AdS-CD/TKrep viral DNA. Ad5-CD/TKrep viral DNA was detected in all major organs of the adult male urogenital tract and liver 7 and 28 Days postinjection. Interestingly, relative to the replication-defective Ad5-FGNR adenovirus, the replication-competent Ad5-CD/TKrep virus accumulated to a much greater level (approximately 300-fold) and persisted for a longer period of time in prostate, testes, and liver. This difference could not be explained on the basis of differences in viral infectivity, suggesting that the AdS-CD/TKrep virus may be capable of replicating in mouse tissues in vivo. In vitro infection of six mouse cell lines representing prostate, testes, and liver demonstrated that the Ad5-CD/TKrep virus was indeed capable of replicating in these mouse cell types, albeit with reduced efficiencies relative to human cells. Despite the fact that the Ad5-CD/TKrep vector persisted in the adult male gonads and may have replicated in vivo, we observed no evidence of germ-line transmission in 149 offspring examined. To evaluate the toxicity of combining Ad5-CD/TKrep viral therapy with CD/5-FC and HSV-1 TK/GCV suicide gene therapies as a prerequisite for a human trial, an escalating dose (10(8), 10(9), 10(10) vp) of Ad5-CD/TKrep was administered intraprostatically followed by 7 days of 5-FC and GCV double prodrug therapy. Although the virus persisted in the mouse urogenital tract and liver for up to 28 days postinjection, most of the toxicities observed were expected, minimal, and self-limiting. These results lead us to believe that intraprostatic administration of the Ad5-CD/TKrep virus to humans concomitant with double suicide gene therapy will be associated with acceptable toxicities and will not result in vertical transmission of viral-encoded genes through the germ line.
Mol Ther 2000 Mar
PMID:Evaluation of the biodistribution, persistence, toxicity, and potential of germ-line transmission of a replication-competent human adenovirus following intraprostatic administration in the mouse. 1093 42


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