Cell transformation by the adenovirus oncogenes E1 and E4

Ip, Wing Hang; Dobner, Thomas

doi:10.1002/1873-3468.13717

Cited by 21 publications

(20 citation statements)

References 156 publications

(91 reference statements)

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“…Some or all of these activities stimulate DDR proteins and/or DDR activities that limit Ad progeny production ( 20 ). Because of this, Ad encodes 3 gene-products that act to nullify the effects of the induced DDR: early region 1B55K (E1B55K), early region 4 open reading frame 6 (E4orf6), and early region 4 open reading frame 3 (E4orf3) that separately have been shown to help E1A to more efficiently transform cells ( 21 – 23 ). Ad E1B55K forms a complex with E4orf6 and together with other cellular factors induces the degradation of numerous DDR proteins, including MRE11 ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Disruption of NBS1/MRN Complex Formation by E4orf3 Supports NF-κB That Licenses E1B55K-Deleted Adenovirus-Infected Cells to Accumulate DNA>4n

et al. 2022

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Genome instability, a hallmark of cancer, exists as part of a cycle that leads to DNA damage and DNA > 4n that further enhances genome instability. Ad E4orf3 is a viral oncogene. Here, we describe E4orf3 mediated signaling events that support DNA > 4n in Δ E1B Ad-infected cells. These signaling events may be linked to the oncogenic potential of E4orf3 and may provide a basis for how some cells survive with DNA > 4n.

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Section: Introductionmentioning

confidence: 99%

Disruption of NBS1/MRN Complex Formation by E4orf3 Supports NF-κB That Licenses E1B55K-Deleted Adenovirus-Infected Cells to Accumulate DNA>4n

et al. 2022

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“…It is well known that the interaction of both Ad2/Ad5 and Ad12 E1B55K with p53 inhibits its transcriptional transactivating properties, which is considered to be important for efficient transformation [64]. However, it has also been demonstrated that properties of E1B55K, other than association with p53, contribute to transformation of rodent cells by AdE1 [64][65][66][67]. It was suggested that an interaction with the MRN complex, as well as an ability to form multi-protein complexes, could be factors favoring the transformation process [66].…”

Section: Discussionmentioning

confidence: 99%

The Promotion of Genomic Instability in Human Fibroblasts by Adenovirus 12 Early Region 1B 55K Protein in the Absence of Viral Infection

Abualfaraj

Hagkarim

Hollingworth

et al. 2021

Viruses

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The adenovirus 12 early region 1B55K (Ad12E1B55K) protein has long been known to cause non-random damage to chromosomes 1 and 17 in human cells. These sites, referred to as Ad12 modification sites, have marked similarities to classic fragile sites. In the present report we have investigated the effects of Ad12E1B55K on the cellular DNA damage response and on DNA replication, considering our increased understanding of the pathways involved. We have compared human skin fibroblasts expressing Ad12E1B55K (55K+HSF), but no other viral proteins, with the parental cells. Appreciable chromosomal damage was observed in 55K+HSFs compared to parental cells. Similarly, an increased number of micronuclei was observed in 55K+HSFs, both in cycling cells and after DNA damage. We compared DNA replication in the two cell populations; 55K+HSFs showed increased fork stalling and a decrease in fork speed. When replication stress was introduced with hydroxyurea the percentage of stalled forks and replication speeds were broadly similar, but efficiency of fork restart was significantly reduced in 55K+HSFs. After DNA damage, appreciably more foci were formed in 55K+HSFs up to 48 h post treatment. In addition, phosphorylation of ATM substrates was greater in Ad12E1B55K-expressing cells following DNA damage. Following DNA damage, 55K+HSFs showed an inability to arrest in cell cycle, probably due to the association of Ad12E1B55K with p53. To confirm that Ad12E1B55K was targeting components of the double-strand break repair pathways, co-immunoprecipitation experiments were performed which showed an association of the viral protein with ATM, MRE11, NBS1, DNA-PK, BLM, TOPBP1 and p53, as well as with components of the replisome, MCM3, MCM7, ORC1, DNA polymerase δ, TICRR and cdc45, which may account for some of the observed effects on DNA replication. We conclude that Ad12E1B55K impacts the cellular DNA damage response pathways and the replisome at multiple points through protein–protein interactions, causing genomic instability.

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“…These gene products are divided into three subtypes based on their transcription start time, including early, middle and late stages (11). Early gene products are predominantly responsible for coding gene regulation, including the E region, while late gene products are predominantly responsible for coding structural proteins, including the L region (12,13). Among adenovirus subtypes, adenovirus serotype 3 (Ad.3) and adenovirus serotype 5 (Ad.…”

Section: Oncolytic Adenovirusmentioning

confidence: 99%

Oncolytic adenovirus: A tool for reversing the tumor microenvironment and promoting cancer treatment (Review)

2021

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Immunogene therapy can enhance the antitumor immune effect by introducing genes encoding co-stimulation molecules, cytokines, chemokines and tumor-associated antigens into treatment cells or human cells through genetic engineering techniques. Oncolytic viruses can specifically target tumor cells and replicate indefinitely until they kill tumor cells. If combined with immunogene therapy, oncolytic viruses can play a more powerful antitumor role. The high pressure, hypoxia and acidity in the tumor microenvironment (TME) provide suitable conditions for tumor cells to survive. To maximize the potency of oncolytic viruses, various methods are being developed to promote the reversal of the TME, thereby maximizing transmission of replication and immunogenicity. The aim of the present review was to discuss the basic mechanisms underlying the effects of oncolytic adenoviruses on the TME, and suggest how to combine the modification of the adenovirus with the TME to further combat malignant tumors. Contents 1. Introduction 2. Oncolytic adenovirus 3. TME of solid tumors 4. Adenovirus modification combined with immune cells in the TME 5. Adenovirus modification combined with stromal cells in the TME 6. Adenovirus modification combined with immune checkpoints in the TME 7. Outlooks

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Cell transformation by the adenovirus oncogenes E1 and E4

Cited by 21 publications

References 156 publications

Disruption of NBS1/MRN Complex Formation by E4orf3 Supports NF-κB That Licenses E1B55K-Deleted Adenovirus-Infected Cells to Accumulate DNA>4n

Disruption of NBS1/MRN Complex Formation by E4orf3 Supports NF-κB That Licenses E1B55K-Deleted Adenovirus-Infected Cells to Accumulate DNA>4n

The Promotion of Genomic Instability in Human Fibroblasts by Adenovirus 12 Early Region 1B 55K Protein in the Absence of Viral Infection

Oncolytic adenovirus: A tool for reversing the tumor microenvironment and promoting cancer treatment (Review)

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