E1B and E4 oncoproteins of adenovirus antagonize the effect of apoptosis inducing factor

Turner, Roberta L.; Wilkinson, John; Ornelles, David A.

doi:10.1016/j.virol.2014.03.010

Cited by 11 publications

(9 citation statements)

References 112 publications

(148 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Ad E1B-55K and E4orf6 proteins cause degradation of various DDR proteins and E4orf3 expression leads to removal of the MRN DNA damage sensor complex from viral replication centers [ 33 , 38 , 39 ]. Moreover, while Ad was shown to induce parylation, the intracellular distribution of PAR-modified proteins was altered by the E1B-55K and E4orf3 proteins, possibly resulting in further modulation of the DDR [ 73 ]. The virus also utilizes its core protein VII to protect the incoming genome from the DDR [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

The Adenovirus E4orf4 Protein Provides a Novel Mechanism for Inhibition of the DNA Damage Response

et al. 2016

View full text Add to dashboard Cite

The DNA damage response (DDR) is a conglomerate of pathways designed to detect DNA damage and signal its presence to cell cycle checkpoints and to the repair machinery, allowing the cell to pause and mend the damage, or if the damage is too severe, to trigger apoptosis or senescence. Various DDR branches are regulated by kinases of the phosphatidylinositol 3-kinase-like protein kinase family, including ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR). Replication intermediates and linear double-stranded genomes of DNA viruses are perceived by the cell as DNA damage and activate the DDR. If allowed to operate, the DDR will stimulate ligation of viral genomes and will inhibit virus replication. To prevent this outcome, many DNA viruses evolved ways to limit the DDR. As part of its attack on the DDR, adenovirus utilizes various viral proteins to cause degradation of DDR proteins and to sequester the MRN damage sensor outside virus replication centers. Here we show that adenovirus evolved yet another novel mechanism to inhibit the DDR. The E4orf4 protein, together with its cellular partner PP2A, reduces phosphorylation of ATM and ATR substrates in virus-infected cells and in cells treated with DNA damaging drugs, and causes accumulation of damaged DNA in the drug-treated cells. ATM and ATR are not mutually required for inhibition of their signaling pathways by E4orf4. ATM and ATR deficiency as well as E4orf4 expression enhance infection efficiency. Furthermore, E4orf4, previously reported to induce cancer-specific cell death when expressed alone, sensitizes cells to killing by sub-lethal concentrations of DNA damaging drugs, likely because it inhibits DNA damage repair. These findings provide one explanation for the cancer-specificity of E4orf4-induced cell death as many cancers have DDR deficiencies leading to increased reliance on the remaining intact DDR pathways and to enhanced susceptibility to DDR inhibitors such as E4orf4. Thus DDR inhibition by E4orf4 contributes both to the efficiency of adenovirus replication and to the ability of E4orf4 to kill cancer cells.

show abstract

Section: Discussionmentioning

confidence: 99%

The Adenovirus E4orf4 Protein Provides a Novel Mechanism for Inhibition of the DNA Damage Response

et al. 2016

View full text Add to dashboard Cite

show abstract

“…As a consequence it has been used to facilitate the display proteins on the surface of the viron (Meulenbroek et al, 2004). In contrast it has recently been demonstrated that pE1b_55K is involved in the inhibition of apoptosis inducing factor to prolong the life of infected cells (Turner et al, 2014). Given these somewhat disparate roles in AdV infection it would seem unlikely the pIX_E1b_55K fusion acts as a multiple function protein.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of the Equine adenovirus 2 genome

Giles

Vanniasinkam

Barton

et al. 2015

Veterinary Microbiology

View full text Add to dashboard Cite

“…FG12-derived plasmids for targeting of AIF and LacZ by RNA interference (RNAi) have been rigorously assessed and used as described [ 28 , 48 , 49 ]. Lentiviral packaging plasmids pRRE, pRSV-rev, and pHCMV-G are as described [ 50 ].…”

Section: Methodsmentioning

confidence: 99%

Basal metabolic state governs AIF-dependent growth support in pancreatic cancer cells

Scott

Wilkinson

2016

BMC Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundApoptosis-inducing factor (AIF), named for its involvement in cell death pathways, is a mitochondrial protein that regulates metabolic homeostasis. In addition to supporting the survival of healthy cells, AIF also plays a contributory role to the development of cancer through its enzymatic activity, and we have previously shown that AIF preferentially supports advanced-stage prostate cancer cells. Here we further evaluated the role of AIF in tumorigenesis by exploring its function in pancreatic cancer, a disease setting that most often presents at an advanced stage by the time of diagnosis.MethodsA bioinformatics approach was first employed to investigate AIF mRNA transcript levels in pancreatic tumor specimens vs. normal tissues. AIF-deficient pancreatic cancer cell lines were then established via lentiviral infection. Immunoblot analysis was used to determine relative protein quantities within cells. Cell viability was measured by flow cytometry; in vitro and Matrigel™ growth/survival using Coulter™ counting and phase contrast microscopy; and glucose consumption in the absence and presence of Matrigel™ using spectrophotometric methods.ResultsArchival gene expression data revealed a modest elevation of AIF transcript levels in subsets of pancreatic tumor specimens, suggesting a possible role in disease progression. AIF expression was then suppressed in a panel of five pancreatic cancer cell lines that display diverse metabolic phenotypes. AIF ablation selectively crippled the growth of cells in vitro in a manner that directly correlated with the loss of mitochondrial respiratory chain subunits and altered glucose metabolism, and these effects were exacerbated in the presence of Matrigel™ substrate. This suggests a critical metabolic role for AIF to pancreatic tumorigenesis, while the spectrum of sensitivities to AIF ablation depends on basal cellular metabolic phenotypes.ConclusionsAltogether these data indicate that AIF supports the growth and survival of metabolically defined pancreatic cancer cells and that this metabolic function may derive from a novel mechanism so far undocumented in other cancer types.

show abstract

E1B and E4 oncoproteins of adenovirus antagonize the effect of apoptosis inducing factor

Cited by 11 publications

References 112 publications

The Adenovirus E4orf4 Protein Provides a Novel Mechanism for Inhibition of the DNA Damage Response

The Adenovirus E4orf4 Protein Provides a Novel Mechanism for Inhibition of the DNA Damage Response

Characterisation of the Equine adenovirus 2 genome

Basal metabolic state governs AIF-dependent growth support in pancreatic cancer cells

Contact Info

Product

Resources

About