Adenovirus Type 5 E4 Open Reading Frame 4 Protein Induces Apoptosis in Transformed Cells

Shtrichman, Ronit; Kleinberger, Tamar

doi:10.1128/jvi.72.4.2975-2982.1998

Cited by 125 publications

(47 citation statements)

References 55 publications

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“…Adenovirus E4orf4 protein is a multifunctional protein. Our work, as well as work from other laboratories, has shown that the E4orf4 protein down regulates expression of genes that have been activated by E1A and cAMP (MuÈ ller et al, 1992;Kleinberger and Shenk, 1993), induces hypophosphorylation of various viral and cellular proteins (MuÈ ller et al, 1992;Kanopka et al, 1998), regulates alternative splicing of adenovirus mRNAs (Kanopka et al, 1998), and induces p53-independent apoptosis in transformed cells Marcellus et al, 1998;Shtrichman and Kleinberger, 1998). We have previously shown that E4orf4 interacts with the PP2A holoenzyme through a direct association with the a isoform of the B subunit (Ba) (Kleinberger and Shenk, 1993).…”

Section: Introductionsupporting

confidence: 53%

Adenovirus E4orf4 protein interacts with both Bα and B′ subunits of protein phosphatase 2A, but E4orf4-induced apoptosis is mediated only by the interaction with Bα

Shtrichman¹,

Sharf²,

Kleinberger³

2000

Oncogene

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Adenovirus E4orf4 protein is a multifunctional viral regulator, which is involved in down regulation of virally-modulated signal transduction, in control of alternative splicing of viral mRNAs, and in induction of apoptosis in transformed cells. It has been previously shown that E4orf4 interacts with protein phosphatase 2A through the phosphatase Balpha subunit. It was further shown that PP2A is required for performing the various E4orf4 functions. We report here that E4orf4 interacts with multiple isoforms of the PP2A-B' subunit, as well as with Balpha. We map the interaction sites of the B subunits on E4orf4 and show that they overlap but are not identical. We identify a dominant negative E4orf4 mutant, which disrupts the PP2A holoenzyme. We show that induction of apoptosis by E4orf4, which we previously reported to require the interaction with Balpha, is not affected by the interaction with B'. Our results suggest that the interaction of E4orf4 with various PP2A subpopulations may mediate the different E4orf4 functions.

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Section: Introductionsupporting

confidence: 53%

Adenovirus E4orf4 protein interacts with both Bα and B′ subunits of protein phosphatase 2A, but E4orf4-induced apoptosis is mediated only by the interaction with Bα

Shtrichman¹,

Sharf²,

Kleinberger³

2000

Oncogene

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“…E4orf6 MUTANT ANALYSIS sively antagonizes cellular transformation through a unique p53-independent mechanism (25,32,53,54). Recently, we and others have shown that the Ad5 E4orf6 and E4orf3 gene products exhibit E1B-like transforming prop-erties in that they can individually cooperate with Ad5 E1A to initiate focus formation in primary baby rat kidney (BRK) cells.…”

Section: Vol 74 2000mentioning

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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“…Recently, we and others have shown that expression of the Ad E4orf4 protein in several mammalian cell lines induces a p53-independent apoptotic pathway (Shtrichman and Kleinberger 1998;Lavoie et al 1998; Marcellus et al 1998). E4orf4 appears to kill transformed cells more selectively, as expression of oncogene in primary cell cultures was reported to sensitize these cells to E4orf4-induced apoptosis (Shtrichman et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Adenovirus E4 Open Reading Frame 4–Induced Apoptosis Involves Dysregulation of Src Family Kinases

Lavoie

Champagne

Gingras

et al. 2000

The Journal of Cell Biology

153

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The adenoviral early region 4 open reading frame 4 (E4orf4) death factor induces p53-independent apoptosis in many cell types and appears to kill selectively transformed cells. Here we show that expression of E4orf4 in transformed epithelial cells results in early caspase-independent membrane blebbing, associated with changes in the organization of focal adhesions and actin cytoskeleton. Evidence that E4orf4 can associate with and modulate Src family kinase activity, inhibiting Src-dependent phosphorylation of focal adhesion kinase (FAK) and paxillin while increasing phosphorylation of cortactin and some other cellular proteins, is presented. Furthermore, E4orf4 dramatically inhibited the ability of FAK and c-src to cooperate in induction of tyrosine phosphorylation of cellular substrates, suggesting that E4orf4 can interfere with the formation of a signaling complex at focal adhesion sites. Consistent with a functional role for E4orf4–Src interaction, overexpression of activated c-src dramatically potentiated E4orf4-induced membrane blebbing and apoptosis, whereas kinase dead c-src constructs inhibited E4orf4 effects on cell morphology and death. Moreover treatment of E4orf4-expressing cells with PP2, a selective Src kinase inhibitor, led to inhibition of E4orf4-dependent membrane blebbing and later to a marked decrease in E4orf4-induced nuclear condensation. Taken together, these observations indicate that expression of adenovirus 2 E4orf4 can initiate caspase-independent extranuclear manifestations of apoptosis through a modulation of Src family kinases and that these are involved in signaling E4orf4-dependent apoptosis. This study also suggests that Src family kinases are likely to play a role in the cytoplasmic execution of apoptotic programs.

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Adenovirus Type 5 E4 Open Reading Frame 4 Protein Induces Apoptosis in Transformed Cells

Cited by 125 publications

References 55 publications

Adenovirus E4orf4 protein interacts with both Bα and B′ subunits of protein phosphatase 2A, but E4orf4-induced apoptosis is mediated only by the interaction with Bα

Adenovirus E4orf4 protein interacts with both Bα and B′ subunits of protein phosphatase 2A, but E4orf4-induced apoptosis is mediated only by the interaction with Bα

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

Adenovirus E4 Open Reading Frame 4–Induced Apoptosis Involves Dysregulation of Src Family Kinases

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