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

Adenovirus (Ad) vectors are most potent for use as gene delivery vehicles to infect human cells in vitro and in vivo with high efficiency. The main limitation in utilization of Ad as a gene transfer vector is the lack of specificity. Genetic modifications of Ad capsid proteins resulting in incorporation of foreign polypeptide ligand sequences can redirect the vector towards target cells. However, in many cases the incorporated ligands lose specificity or lead to conformational changes influencing virion integrity. In order to select target-specific ligands a priori structurally compatible with Ad, we propose a system for displaying polypeptide sequences in the context of the Ad fiber knob on the surfaces of filamentous bacteriophages. To establish this concept, we displayed the wild-type Ad serotype 5 knob and knobs containing c-Myc epitopes and six-histidine sequences in the pJuFo phage system. The knobs remained trimeric and bound the coxsackievirus-Ad receptor, and the phage knob-displayed ligands recognized and bound their cognates in the phage-displayed knob context. Further development of this system may be useful for candidate ligand fidelity and Ad structural compatibility validation prior to Ad modification.
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PMID:Phage display of adenovirus type 5 fiber knob as a tool for specific ligand selection and validation. 1143 91

Insulin biosynthesis and secretion are critical for pancreatic beta-cell function, but both are impaired under diabetic conditions. We have found that hyperglycemia induces the expression of the basic helix-loop-helix transcription factor c-Myc in islets in several different diabetic models. To examine the possible implication of c-Myc in beta-cell dysfunction, c-Myc was overexpressed in isolated rat islets using adenovirus. Adenovirus-mediated c-Myc overexpression suppressed both insulin gene transcription and glucose-stimulated insulin secretion. Insulin protein content, determined by immunostaining, was markedly decreased in c-Myc-overexpressing cells. In gel-shift assays c-Myc bound to the E-box in the insulin gene promoter region. Furthermore, in betaTC1, MIN6, and HIT-T15 cells and primary rat islets, wild type insulin gene promoter activity was dramatically decreased by c-Myc overexpression, whereas the activity of an E-box mutated insulin promoter was not affected. In HeLa and HepG2 cells c-Myc exerted a suppressive effect on the insulin promoter activity only in the presence of NeuroD/BETA2 but not PDX-1. Both c-Myc and NeuroD can bind the E-box element in the insulin promoter, but unlike NeuroD, the c-Myc transactivation domain lacked the ability to activate insulin gene expression. Additionally p300, a co-activator of NeuroD, did not function as a co-activator of c-Myc. In conclusion, increased expression of c-Myc in beta-cells suppresses the insulin gene transcription by inhibiting NeuroD-mediated transcriptional activation. This mechanism may explain some of the beta-cell dysfunction found in diabetes.
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PMID:Induction of c-Myc expression suppresses insulin gene transcription by inhibiting NeuroD/BETA2-mediated transcriptional activation. 1179 23

Adenovirus (Ad) E1A proteins are transcriptional regulators with antioncogenic but also transforming properties. We have previously shown that transformation-defective Ad5 E1A-derivatives are excellent tumor suppressors. For tumor-specific expression of the E1A-derivatives we intend to use tumor specific human telomerase reverse transcriptase (hTERT) core promoters. Here, we show that Spm2 and other E1A proteins with an intact amino terminus activated all hTERT constructs 10-20-fold in malignant tumor cells but not in primary fibroblasts, without affecting the activity of endogenous telomerase. The transcription rate in tumor cells was in the range of transcription from the SV40 promoter, which qualifies an E1A-hTERT system as a putative tumor targeting/expression system. The activation of the hTERT promoter by E1A was enhanced upon deletion of the Wilms' tumor 1 negative regulatory element and maintained high after deletion of the adjacent c-Myc-responsive E-box, demonstrating an important role of the remaining sequences that contain several Sp1-motifs. E1A-mediated hTERT activation was independent from the presence of the conserved region 3 (CR3) of E1A but dependent on E1A's binding to p300/CBP and recruitment of its histone acetyltransferase activity. Moreover, E1A-Spm2 and histone deacetylase-1 behaved as antagonists with respect to the regulation of transcription from the hTERT promoter. Overall, hTERT promoter/E1A-Spm2 systems may turn out to be excellent tools for transcriptionally targeted anticancer gene therapy.
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PMID:Tumor-specific activation of hTERT-derived promoters by tumor suppressive E1A-mutants involves recruitment of p300/CBP/HAT and suppression of HDAC-1 and defines a combined tumor targeting and suppression system. 1243 49

Adenovirus E1A oncogene transforms primary rodent fibroblasts in cooperation with activated Ras. Conversely, the c-Myc oncoprotein-binding tumor suppressor, Bin1, inhibits Ras/E1A-mediated cell transformation. Since E1A does not directly bind to and inhibit Bin1, the primary mechanism by which E1A counteracts Bin1 to liberate oncogenic c-Myc activity is poorly understood. Here we show that wild-type E1A, but not an Rb binding-defective E1A mutant, suppresses endogenous Bin1 expression in cultured rodent fibroblasts. Similarly, other anti-Rb agents, such as human papillomavirus E7, mitogenic stimuli, and small interfering RNA (siRNA) for Rb, consistently decrease Bin1 promoter activity. In contrast, serum starvation, which activates Rb, enhances endogenous Bin1 levels. These findings suggest that Bin1 may be a novel component of Rb-mediated G1 arrest. Consistent with this premise, chromatin immunoprecipitation assays demonstrate that Rb protein directly interacts with the Bin1 promoter only upon removal of serum. Furthermore, ectopically expressed E2F1, which is primarily inhibited by Rb under serum-starved condition, represses Bin1 promoter activity in a manner that is dependent on the DNA-binding and transactivation domains of E2F1. Lastly, depletion of endogenous Bin1 per se is biologically meaningful since antisense or siRNA of Bin1 transfection releases endogenous c-Myc transcriptional activity and, concomitantly, accelerates cell proliferation. Our results suggest that Bin1 gene suppression caused by oncogenic E1A via Rb inactivation is an essential step in cell cycle progression promoted by c-Myc, and subsequently, E1A transformation. We propose a novel G1 arrest signaling mechanism by which Rb indirectly curbs oncogenic c-Myc activity via sustaining Bin1 expression.
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PMID:Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism. 1834 66