The E4-6/7 Protein Functionally Compensates for the Loss of E1A Expression in Adenovirus Infection

O'Connor, R J; Hearing, Patrick

doi:10.1128/jvi.74.13.5819-5824.2000

Cited by 35 publications

(26 citation statements)

References 40 publications

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“…1 Free E2F also binds to the inverted E2F binding sites in the viral E2a promoter and induces expression of viral E2 genes that are essential for viral DNA replication and important for viral late gene expression. 2 To prevent the spread of viral infection, host cells have developed several strategies to impede viral replication. One of the well-studied cellular responses is the activation of p53-mediated apoptosis and cell growth arrest.…”

Section: T O Induce the Cells Into S-phase For Effective Viralmentioning

confidence: 99%

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

et al. 2004

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Apoptotic pathways are initiated as a cellular defense mechanism to eliminate adenovirus-infected cells. We have investigated how E1A-induced apoptosis interferes with viral replication in cancer cells. We found that E1B19K alone can efficiently suppress E1A-induced apoptosis in cancer cells. Viruses deleted for both E1B19K and E1B55K resulted in cellular DNA degradation. However, less than 20% of human lung cancer cells infected with a virus deleted for both E1B19K and E1B55 K had evidence of chromatin condensation and multiple-micronuclei formation (apoptotic hallmarks); these cells could not produce infectious viral particles. The majority of cancer cells infected with viruses deleted for the entire E1b gene did not undergo extended apoptosis and produced abundant viral progeny. Thus, only a fraction of cancer cells underwent apoptosis and did not allow E1b-deleted viruses to replicate, while the majority of cancer cells were resistant to E1A-induced apoptosis and could support virus-selective replication. The results of this study imply that, in addition to inhibiting E1A-induced apoptosis, E1B proteins may contribute other important roles in the viral life cycle. Our results also suggest that combining virus-induced apoptosis and selective viral replication into one vector will be a novel approach to destroy cancer cells.

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Section: T O Induce the Cells Into S-phase For Effective Viralmentioning

confidence: 99%

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

et al. 2004

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“…This observation, which has been made previously (22), implies either a nonspecific inflammatory effect of adenoviral proteins or possible low level replication. The latter has been shown in tumor cells infected with E1-deleted viruses (23), which may be due to abnormalities in G 2 -M cell cycle checkpoint in malignant cells (23) or genes present in the remainder of the genome that partially compensate for the loss of E1, such as E4orf6/7, which can also disrupt the interaction between pRb and E2F (24).…”

Section: Discussionmentioning

confidence: 99%

Activity of the Adenoviral E1A Deletion Mutant dl922-947 in Ovarian Cancer: Comparison with E1A Wild-type Viruses, Bioluminescence Monitoring, and Intraperitoneal Delivery in Icodextrin

et al. 2006

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The adenoviral mutant dl922-947 has potent activity in a variety of tumors. We investigated the efficacy of dl922-947 in ovarian carcinoma; compared its activity to wild-type adenovirus, dl309, and dl1520; and investigated the use of icodextrin to enhance activity in vivo. We also assessed the utility of luciferase bioluminescence imaging to quantify the response of human ovarian carcinoma xenografts to dl922-947. Ovarian carcinoma cell lines were transfected in vitro with dl922-947, adenovirus 5 wild-type (Ad5 WT), dl309, and dl1520 and monitored for S-phase induction, viral protein expression, replication, and overall survival. In vivo, the efficacy of dl922-947 when delivered in PBS or icodextrin to female nude mice bearing IGROV1 xenografts was determined. In vitro, dl922-947 induced lysis with greater efficacy than Ad5 WT, dl309, or dl1520 in all ovarian carcinoma cell lines tested, which was associated with earlier expression of viral proteins and S-phase induction. The lytic effect in immortalized ovarian surface epithelial cells confirmed that cellular retinoblastoma pathway status is a strong determinant of dl922-947 activity. In vivo, i.p. delivery of dl922-947 (5 Â 10 9 particles daily Â 5) increased median survival from 20 to 96 days (P < 0.0001) and delivery in icodextrin-enhanced survival further. However, delayed hepatic toxicity was evident in some dl922-947-treated mice, which was not dependent upon viral replication within tumor cells or the liver. dl922-947 has potency in ovarian carcinoma and i.p. delivery in icodextrin may enhance this activity. Immunocompetent models of ovarian carcinoma are required for further evaluation of hepatotoxicity. (Cancer Res 2006; 66(2): 989-98)

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“…Another possibility is that E4 gene products also play a role in MAV-1 replication. The human adenovirus E4 ORF6/7 protein has been shown to induce E2F DNA binding to the viral E2A promoter and thus functionally compensate for the loss of E1A in human adenovirus infection (44,49). MAV-1 E4 ORFd (36) has 17% identity and 43% similarity to human adenovirus E4 ORF6/7 protein (L. Fang and K. R. Spindler, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Requirement of Sur2 for Efficient Replication of Mouse Adenovirus Type 1

Fang

Stevens

Berk

et al. 2004

J Virol

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Mouse adenovirus type 1 (MAV-1) early region 1A (E1A) encodes a virulence gene in viral infection of mice. To broaden our understanding of the functions of E1A in MAV-1 pathogenesis, an unbiased experimental approach, glutathione S-transferase (GST) pulldown, was used to screen for cellular proteins that interact with E1A protein. We identified mouse Sur2, a subunit of Mediator complex, as a protein that binds to MAV-1 E1A. The interaction between Sur2 and MAV-1 E1A was confirmed in virus-infected cells. Conserved region 3 (CR3) of MAV-1 E1A was mapped as the region required for Sur2-E1A interaction, as is the case for human adenovirus E1A. Although it has been proposed that human adenovirus E1A recruits the Mediator complex to transactivate transcription of viral early genes, Sur2 function in adenovirus replication has not been directly tested previously. Studies on the functions of Sur2 with mouse embryonic fibroblasts (MEFs) showed that there was a multiplicity-dependent growth defect of MAV-1 in Sur2 ؊/؊ MEFs compared to Sur2 ؉/؉ MEFs. Comparison of the viral DNA and viral mRNA levels in Sur2 ؉/؉ and Sur2 ؊/؊ MEFs confirmed that Sur2 was important for efficient viral replication. The viral replication defects in Sur2 ؊/؊ MEFs appeared to be due at least in part to a defect in viral early gene transcription.

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The E4-6/7 Protein Functionally Compensates for the Loss of E1A Expression in Adenovirus Infection

Cited by 35 publications

References 40 publications

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

Activity of the Adenoviral E1A Deletion Mutant dl922-947 in Ovarian Cancer: Comparison with E1A Wild-type Viruses, Bioluminescence Monitoring, and Intraperitoneal Delivery in Icodextrin

Requirement of Sur2 for Efficient Replication of Mouse Adenovirus Type 1

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