ArticleJournal of virology2014
Hijacking Dlg1 for oncogenic phosphatidylinositol 3-kinase activation in human epithelial cells is a conserved mechanism of human adenovirus E4-ORF1 proteins.
Article in Journal of virology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 23 citations in OpenAlex.
- The adenovirus E4orf1 protein initiates a feedback loop involving insulin and growth factor receptors, AKT, and NF-κB, leading to abnormal DNA content in infected cells.PLoS pathogens · 2025Article
- In Silico Intensive Analysis for the E4 Gene Evolution of Human Adenovirus Species D.Journal of microbiology (Seoul, Korea) · 2024Article
- The human adenovirus PI3K-Akt activator E4orf1 is targeted by the tumor suppressor p53.Journal of virology · 2024Article
- Findings from Studies Are Congruent with Obesity Having a Viral Origin, but What about Obesity-Related NAFLD?Viruses · 2021Review
- Characterization of the adipogenic protein E4orf1 from adenovirus 36 through an in silico approach.Journal of molecular modeling · 2020Article
- How Viral and Intracellular Bacterial Pathogens Reprogram the Metabolism of Host Cells to Allow Their Intracellular Replication.Frontiers in cellular and infection microbiology · 2019Review
- Upsetting the Balance: When Viruses Manipulate Cell Polarity Control.Journal of molecular biology · 2018Review
- E4orf1: A protein for enhancing glucose uptake despite impaired proximal insulin signaling.PloS one · 2018Article
- Somatic PI3K activity regulates transition to the spermatocyte stages in Drosophila testis.Journal of biosciences · 2017Article
- The high-risk HPV E6 target scribble (hScrib) is required for HPV E6 expression in cervical tumour-derived cell lines.Papillomavirus research (Amsterdam, Netherlands) · 2016Article
- Review
- An adenovirus-derived protein: A novel candidate for anti-diabetic drug development.Biochimie · 2016Article
- Viral Interactions with PDZ Domain-Containing Proteins-An Oncogenic Trait?Pathogens (Basel, Switzerland) · 2016Review
- Adenovirus E4-ORF1 Dysregulates Epidermal Growth Factor and Insulin/Insulin-Like Growth Factor Receptors To Mediate Constitutive Myc Expression.Journal of virology · 2015Article
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3 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledThe E4-ORF1 gene of human adenoviruses encodes a 14-kDa protein that promotes viral replication as well as cellular metabolic reprogramming, survival, and transformation by constitutively activating cellular phosphatidylinositol 3-kinase (PI3K). We recently reported that the E4-ORF1 protein from subgroup D human adenovirus type 9 upregulates and oncogenically activates PI3K by a novel mechanism involving separate interactions of E4-ORF1 with cellular discs large 1 (Dlg1) and PI3K to form a ternary complex that translocates to the plasma membrane (K. Kong, M. Kumar, M. Taruishi, and R. T. Javier, PLoS Pathog. 10:e1004102, 2014, doi:10.1371/journal.ppat.1004102). The current study was carried out to investigate whether other human adenovirus E4-ORF1 proteins share this mechanism of action. The results showed that in human MCF10A epithelial cells, stable expression of E4-ORF1 proteins encoded by representative human adenovirus serotypes from subgroups A to D induce ternary complex formation, Dlg1-dependent PI3K activation, PI3K protein elevation, Dlg1 and PI3K membrane recruitment, and PI3K-dependent cellular transformation. The first three of these E4-ORF1 activities were also observed in MCF10A cells infected with each wild-type human adenovirus from subgroups A to D. Our findings indicate that most, if not all, human adenovirus E4-ORF1 proteins share a conserved molecular mechanism of PI3K activation, which confers a common capacity to promote oncogenic transformation in human epithelial cells. IMPORTANCE: PI3K activation by the adenovirus E4-ORF1 protein mediates oncogenic cellular transformation by human adenovirus type 9, augments viral protein expression and replication by human adenovirus type 5, and dysregulates cellular glucose and lipid metabolism by human adenovirus type 36. For the first time, we report that E4-ORF1 proteins from human adenoviruses in subgroups A to D evolved a conserved molecular mechanism to mediate constitutive PI3K activation that can provoke oncogenic transformation in human epithelial cells. The results raise potential safety concerns about the use of vectors encoding the E4-ORF1 gene in human gene therapy and vaccination. Our findings further suggest that the conserved mechanism revealed here may be targeted for development of therapeutic drugs to treat and prevent adenovirus-associated human diseases.
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