The adenovirus type 5 E1A enhancer contains two functionally distinct domains: One is specific for E1A and the other modulates all early units in cis

Hearing, Patrick; Shenk, Thomas

doi:10.1016/0092-8674(86)90387-9

Cited by 112 publications

(122 citation statements)

References 37 publications

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“…The wild-type E1A enhancer contains two types of regulatory element, termed I and II, 20 which overlap the packGene Therapy aging signal (Figure 1a). In addition to these elements, there are transcription factor binding sites in the inverted terminal repeat (ITR) and close to the E1A TATA box.…”

Section: E1a Promoter Mutationsmentioning

confidence: 99%

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Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway

Fuerer

Iggo

2002

Gene Ther

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Section: E1a Promoter Mutationsmentioning

confidence: 99%

“…The reduced activity of these viruses in permissive cells might be due to deletion of element II in the E1A enhancer, which was previously reported to activate transcription of all of the early promoters in cis. 20 …”

Section: Figure 7 Cytopathic Effect Assays In Different Cell Lines Inmentioning

confidence: 99%

Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway

Fuerer

Iggo

2002

Gene Ther

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“…First, promoter fidelity might be abolished by the upstream adenoviral packaging sequence that contains two enhancer elements of the E1A promoter, which are active in most cell types tested and essential for adenoviral encapsidation. [20][21][22][23] Second, already small amounts of E1A gene products are sufficient to initiate adenoviral replication. 24 In addition, E1A inframe deletion mutants have been reported that support viral growth in tumor cells but not in normal cells.…”

mentioning

confidence: 99%

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

et al. 2003

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Replication-competent adenoviral vectors hold the promise to be more efficient gene delivery vehicles than their replicationdeficient counterparts, but they are also associated with a higher risk for adverse effects, especially in light of the fact that there is no established effective therapy for serious, disseminated adenovirus infection. To assess whether the therapeutic options to inhibit adenoviral replication can be enhanced by expressing a suicide gene, we examined the antiadenoviral effects of 15 drugs against wild-type adenovirus type 5 (Ad5) and an Ad5-based replication-competent vector expressing herpes simplex virus-1 thymidine kinase (HSV-tk) (Ad.OW34) using a real-time polymerase chain reaction -based assay and flow cytometry. Ad5 and Ad.OW34 were highly susceptible to the fluorinated pyrimidine analogs 5-fluoro-2 0 -deoxyuridine (FUdR), 5-fluorouridine (FUR), and trifluorothymidine (TFT), with a mean 50% inhibitory concentration (IC 50 ) ranging from 0.12 to 0.32 mM. The mean IC 50 of ribavirin and cidofovir (CDV) for Ad5, the most frequently used drugs to treat adenovirus disease, was 6.87 and 3.19 mM, respectively. In contrast to Ad5, the Ad.OW34 vector was susceptible to (E)-5-(2-bromovinyl)-2 0 -deoxyuridine (BVdU, IC 50 0.09 mM), ganciclovir (GCV, IC 50 0.19 mM), and acyclovir (ACV, IC 50 32.04 mM). Additionally, we demonstrated in an animal model that Ad.OW34 vector replication can be inhibited significantly by GCV, CDV, and TFT by 35.2, 7.7, and 3.7-fold, respectively, compared to untreated animals. The observed antiadenoviral effects were primarily not through cell killing, since the in vitro 50% cytotoxic concentrations (CC 50 ) were more than 1000 times higher than the antiadenoviral IC 50 of the drugs examined, even in cells stably expressing HSV-tk. Since for HSV-tk-dependent inhibition of adenoviral vectors, stability of HSV-tk expression is crucial, we examined Ad.OW34 vector stability, by passaging the vector 10 times serially in the presence of 10 mM GCV. The HSV-tk/GCV system neither changed the susceptibility of Ad.OW34 to GCV significantly nor detectable vector rearrangements occurred, suggesting that the system might be suitable as a fail-safe mechanism to stop adenoviral vector replication.

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“…3 The E1A enhancer contains two functionally distinct domains, one is specific for E1A (nt 200-300) and the other transactivates all early units (nt 250-280). [6][7][8] The upstream half of the E1A enhancer appears to have a specific conformation critical for its transactivation 9 and represents the binding site for a cellular protein termed EF-1A. The E1A enhancer overlaps physically with cis-acting sequences required for packaging of viral genomes (nt 194-358) 10 and can therefore not be removed from Ad vectors (Figure 1b).…”

Section: Introductionmentioning

confidence: 99%

Insulation from viral transcriptional regulatory elements improves inducible transgene expression from adenovirus vectors in vitro and in vivo

2000

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The adenovirus type 5 E1A enhancer contains two functionally distinct domains: One is specific for E1A and the other modulates all early units in cis

Cited by 112 publications

References 37 publications

Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway

Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

Insulation from viral transcriptional regulatory elements improves inducible transgene expression from adenovirus vectors in vitro and in vivo

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