Human adenovirus type 9 E4 open reading frame 1 encodes a cytoplasmic transforming protein capable of increasing the oncogenicity of CREF cells

Weiss, Robert S.; McArthur, Mark J.; Javier, Ronald T.

doi:10.1128/jvi.70.2.862-872.1996

Cited by 33 publications

(25 citation statements)

References 37 publications

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“…We also tested whether E4‐ORF1 can cause GFP‐Dlg1 to accumulate at the plasma membrane of 293T cells. When expressed alone, GFP‐Dlg1‐I2 and GFP‐Dlg1‐I3 similarly localized diffusely in the cytoplasm (Figure 5D), as did E4‐ORF1, which additionally exhibited characteristic accumulation within cytoplasmic punctae (data not shown) (Weiss et al , 1996). Expression of GFP‐Dlg1‐I3 with E4‐ORF1, however, caused both proteins to translocate to the plasma membrane in ∼70% of transfected cells (Figure 5D).…”

Section: Resultsmentioning

confidence: 92%

Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor

Frese

Latorre

Chung

et al. 2006

EMBO J

110

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The fact that several different human virus oncoproteins, including adenovirus type 9 E4-ORF1, evolved to target the Dlg1 mammalian homolog of the membrane-associated Drosophila discs-large tumor suppressor has implicated this cellular factor in human cancer. Despite a general belief that such interactions function solely to inactivate this suspected human tumor suppressor protein, we demonstrate here that E4-ORF1 specifically requires endogenous Dlg1 to provoke oncogenic activation of phosphatidylinositol 3-kinase (PI3K) in cells. Based on our results, we propose a model wherein E4-ORF1 binding to Dlg1 triggers the resulting complex to translocate to the plasma membrane and, at this site, to promote Rasmediated PI3K activation. These findings establish the first known function for Dlg1 in virus-mediated cellular transformation and also surprisingly expose a previously unrecognized oncogenic activity encoded by this suspected cellular tumor suppressor gene.

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Section: Resultsmentioning

confidence: 92%

Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor

Frese

Latorre

Chung

et al. 2006

EMBO J

110

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“…Further, it was shown that the E4 genes of nononcogenic Ad2 potentiate Ad2 E1-induced focus formation in CREF cells (42) and that the presence of E4 is not only a prerequisite but even the major determinant for the tumorigenic capacity of Ad9 (19,58). The E4 function critical for tumor induction by Ad9 was genetically mapped to E4orf1, which by itself is able to transform CREF cells in vitro (20,62). Recent evidence suggests that the Ad5 E4orf6/7 protein, which is known to interact with the S-phase-specific transcription factor E2F (16), may also positively or negatively influence oncogenesis by induction of transformation or p53dependent apoptosis, respectively (65), while E4orf4 exclu-FIG.…”

mentioning

confidence: 99%

Two Distinct Activities Contribute to the Oncogenic Potential of the Adenovirus Type 5 E4orf6 Protein

Nevels¹,

Rubenwolf²,

Spruß³

et al. 2000

J. Virol.

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Previous studies have shown that the adenovirus type 5 (Ad5) E4orf6 gene product displays features of a viral oncoprotein. It initiates focal transformation of primary rat cells in cooperation with Ad5 E1 genes and confers multiple additional transformed properties on E1-expressing cells, including profound morphological alterations and dramatically accelerated tumor growth in nude mice. It has been reported that E4orf6 binds to p53 and, in the presence of the Ad5 E1B-55kDa protein, antagonizes p53 stability by targeting the tumor suppressor protein for active degradation. In the present study, we performed a comprehensive mutant analysis to assign transforming functions of E4orf6 to distinct regions within the viral polypeptide and to analyze a possible correlation between E4orf6-dependent p53 degradation and oncogenesis. Our results show that p53 destabilization maps to multiple regions within both amino-and carboxy-terminal parts of the viral protein and widely cosegregates with E4orf6-dependent acceleration of tumor growth, indicating that both effects are related. In contrast, promotion of focus formation and morphological transformation require only a carboxyterminal segment of the E4 protein. Thus, these effects are completely independent of p53 stability, but may involve other interactions with the tumor suppressor. Our results demonstrate that at least two distinct activities contribute to the oncogenic potential of Ad5 E4orf6. Although genetically separable, both activities are largely mediated through a novel highly conserved, cysteine-rich motif and a recently described arginine-faced amphipathic alpha helix, which resides within a carboxy-terminal "oncodomain" of the viral protein.

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“…One of these E4 products, E4-ORF6, has been shown to block p53 function and to have oncogenic potential (11,36). A similar cellular transforming or oncogenic function has also been linked to E4-ORF1 (19)(20)(21)(22)(46)(47)(48). E4-ORF6 and E4-ORF3 have also been shown to be involved in altering mRNA expression at a posttranscriptional level (39)(40)(41)(42)(43)(44).…”

mentioning

confidence: 99%

Activation of transgene expression by early region 4 is responsible for a high level of persistent transgene expression from adenovirus vectors in vivo

Brough

Hsu

Kulesa

et al. 1997

J Virol

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The persistence of transgene expression has become a hallmark for adenovirus vector evaluation in vivo.Although not all therapeutic benefit in gene therapy is reliant on long-term transgene expression, it is assumed that the treatment of chronic diseases will require significant persistence of expression. To understand the mechanisms involved in transgene persistence, a number of adenovirus vectors were evaluated in vivo in different strains of mice. Interestingly, the rate of vector genome clearance was not altered by the complete deletion of early region 4 (E4) in our vectors. The GV11 (E1 ؊ E4 ؊ ) vector genome cleared with a similar kinetic profile as the GV10 (E1 ؊ ) vector genome in immunocompetent and immunocompromised mice. These results suggest that the majority of adenovirus vector genomes are eliminated from transduced tissue via a mechanism(s) independent of T-cell, B-cell, and NK cell immune mechanisms. While the levels of persistence of transgene expression in liver or lung transduced with GV10 and GV11 vectors expressing ␤-galactosidase, cystic fibrosis transmembrane conductance regulator, or secretory alkaline phosphatase were similar in immunocompetent mice, a marked difference was observed in immunocompromised animals. Levels of transgene expression initially from both GV10 and GV11 vectors were the same. However, GV11 transgene expression correlated with loss of vector genome, while GV10 transgene expression persisted at a high level. Coadministration and readministration of GV10 vectors showed that E4 provided in trans could activate transgene expression from the GV11 vector genome. While transgene expression activity per genome from the GV10 vector is clearly activated, expression from a cytomegalovirus promoter expression cassette in a GV11 vector appeared to be further inactivated as a function of time. Understanding the molecular mechanisms underlying these expression effects will be important for developing persistent adenovirus vectors for chronic applications.

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Human adenovirus type 9 E4 open reading frame 1 encodes a cytoplasmic transforming protein capable of increasing the oncogenicity of CREF cells

Cited by 33 publications

References 37 publications

Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor

Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor

Two Distinct Activities Contribute to the Oncogenic Potential of the Adenovirus Type 5 E4orf6 Protein

Activation of transgene expression by early region 4 is responsible for a high level of persistent transgene expression from adenovirus vectors in vivo

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