Molecular regulation and biological function of adenovirus early genes: the E4 ORFs

Täuber, Birgitt; Dobner, Thomas

doi:10.1016/s0378-1119(01)00722-3

Cited by 64 publications

(49 citation statements)

References 210 publications

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“…The E4 region of the Ad vectors contains 7 ORFs (E4ORF1, E4ORF2, E4ORF3, E4ORF4, E4ORF3/4, E4ORF6, and E4ORF6/7), encoding 6 distinct polypeptides (6). We showed that adenovirus E4 ϩ vectors, expressing the full complement of E4 gene products, promote PEC survival in the absence of angiogenic factors and serum (7,8).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene

Seandel

Butler

Kobayashi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

128

157

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Section: Resultsmentioning

confidence: 99%

“…The gene products encoded by early region 4 (E4) of adenovirus are essential for virus replication, modulating cell cycle, apoptosis, and cell signaling (6). We have shown that the Ad-E4 gene complex maintains angiogenic properties of PECs, by modulating the migration and apoptosis of PECs (7).…”

mentioning

confidence: 99%

Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene

Seandel

Butler

Kobayashi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

128

157

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show abstract

“…43 However, studies characterizing the function of the E4 gene products led the investigators to conclude that it is 'prudent' to remove all of the E4 region. 44 It is important to remember that with each deletion of a viral gene, a cell line must be created to complement that gene 45 and this can create production issues.…”

Section: Advanced Generations Of Ad Vectors Provide Increased Persistmentioning

confidence: 99%

Gene therapy progress and prospects: adenoviral vectors

George¹

2003

Gene Ther

264

165

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In September 1999, the perceptions of the use of adenoviral (Ad) vectors for gene therapy were altered when a patient exposed via the hepatic artery to a high dose of adenoviral vector succumbed to the toxicity related to vector administration. Appropriately, concerns were raised about continued use of the Ad vector system and, importantly, there were increased efforts to more fully understand the toxicity. Today it is recognized that there is no ideal vector system, and that while Ad vectors are not suitable for all applications, the significant advantages over other vector systems including efficient transduction of a variety of cell types, both quiescent and dividing, make it optimal for certain applications. These include protocols where high levels of short-term expression are sufficient to provide a therapeutic benefit. Potential target applications include therapeutic angiogenesis, administration into immune-privileged sites such as the CNS, or treatments where the adjuvant effect of adenovirus can be of benefit such as cancer vaccines. Broader applicability of Ad vectors will require resolution of toxicity issues. This review will therefore focus on studies conducted over the last 2 years that have advanced our understanding of the toxicity associated with Ad vectors, studies that have employed methods to reduce toxicity and improvements in Ad vectors themselves that will reduce toxicity by one of several mechanisms. These mechanisms include retargeting vector to the tissue of interest, minimizing or eliminating viral gene expression that is thought to result in loss of transduced cells, or by methods that seek to reduce the vector dose required for therapeutic benefit. An area where there remains significant room for improvement is when readministration of vector is required because transgene expression has decreased to background levels.

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“…19,21,42,43 Ad proteins account for the reduction by binding to proteins of the MRN complex leading to their degradation. 19,20,43 MRN inhibition therefore prevents correction of radiation induced double strand breaks and the constant accumulation of mutations eventually makes it impossible for even cancer cells to survive.…”

Section: Discussionmentioning

confidence: 99%

“…Oncolytic Ads inhibit this response by binding of E4orf3, E4orf6 and E1b55K to proteins of the MRN complex, which leads to MRN degradation. 19,20 The interaction of E1b55K/E4orf6 with Mre11 is a key step leading to MRN degradation and to inactivation of its downstream target proteins such as ataxia telangiectasia mutated (ATM), which is involved in DNA-damage signaling. 19,21 MRN complex inhibition prevents correction of radiation induced double strand breaks and their constant accumulation leads to cell death.…”

Section: Uiccmentioning

confidence: 99%

Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation

Rajecki

Hällström

Hakkarainen

et al. 2009

Intl Journal of Cancer

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New treatment approaches are needed for hormone refractory prostate cancer. Oncolytic adenoviruses are promising anti-cancer agents, and their efficacy can be improved by combining with conventional therapies such as ionizing radiation. The aim of this study was to determine the timing of oncolytic adenovirus treatment with regard to radiation and study the mechanisms of synergy in combination treatment. Prostate cancer cells were infected with oncolytic adenoviruses, irradiated and synergy mechanisms were assessed. In vivo models of combination treatment were tested. Radiation and oncolytic viruses were synergistic when viral infection was scheduled 24 hr after irradiation. Combination of oncolytic adenovirus with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone. Microarray analysis showed dysregulated pathways including cell cycle, mTOR and antigen processing pathways. Functional analysis showed that adenoviral infection was accompanied with degradation of proteins involved in DNA break repair. Mre11 was degraded for subsequent inactivation of Chk2-Thr68 in combination treated cells, while cH2AX-Ser139 was elevated implicating the persistence of DNA double strand breaks. Increased autophagocytosis was seen in combination treated cells. Combination treatment did not increase apoptosis or virus replication. The results provide evidence of the antitumor efficacy of combining oncolytic adenoviruses with irradiation as a therapeutic strategy for the treatment of prostate cancer. Further, these findings propose a molecular mechanism that may be important in radiation induced cell death, autophagy and viral cytopathic effect. ' 2009 UICC

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Molecular regulation and biological function of adenovirus early genes: the E4 ORFs

Cited by 64 publications

References 210 publications

Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene

Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene

Gene therapy progress and prospects: adenoviral vectors

Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation

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