Adenovirus E4 Open Reading Frame 4-Induced Dephosphorylation Inhibits E1A Activation of the E2 Promoter and E2F-1-Mediated Transactivation Independently of the Retinoblastoma Tumor Suppressor Protein

Mannervik, Mattias; Fan, Shaoan; Ström, Anne-Christine; Helin, Kristian; Akusjärvi, Göran

doi:10.1006/viro.1999.9663

Cited by 33 publications

(26 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It has been shown that E4orf4 leads to the reduced phosphorylation of different proteins either involved in transcription, or splicing. 83,[87][88][89] The E4orf4-PP2a complex leads to hypophosphorylation of transcription factors c-Fos, E4F, and regulates their transcriptional activity, however, the kinases targeted by the E4orf4-PP2A complex in this process is not known. The complex of E4orf4 also leads to reduced phosphorylation of serine/arginine-rich (SR) proteins, which inhibits IIIA pre-mRNA splicing.…”

Section: E4orf4-another Tumor-selective Killermentioning

confidence: 99%

Cancer-selective therapy of the future: Apoptin and its mechanism of action

Maddika¹,

Mendoza²,

Hauff³

et al. 2006

Cancer Biology & Therapy

View full text Add to dashboard Cite

Section: E4orf4-another Tumor-selective Killermentioning

confidence: 99%

Cancer-selective therapy of the future: Apoptin and its mechanism of action

Maddika¹,

Mendoza²,

Hauff³

et al. 2006

Cancer Biology & Therapy

View full text Add to dashboard Cite

“…2 protein is a multifunctional viral regulator, which down-regulates expression of genes that have been activated by E1A and cAMP (1)(2)(3)(4), induces hypophosphorylation of various viral and cellular proteins (1,5), regulates alternative splicing of adenovirus mRNAs (5), and induces p53-independent apoptosis in transformed cells (6 -8). Oncogenic transformation of primary cells sensitizes them to cell killing by E4orf4 (9), indicating that E4orf4 research may have exciting implications for cancer therapy.…”

Section: Adenovirus E4orf4mentioning

confidence: 99%

YND1 Interacts with CDC55 and Is a Novel Mediator of E4orf4-induced Toxicity

Maoz

Koren

Ben-Ari

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…he adenovirus E4orf4 protein contributes to the progression of viral infection from the early to the late phase (1)(2)(3)(4)(5)(6)(7). When expressed outside the context of virus infection, E4orf4 induces caspase-and p53-independent cell death in transformed cells (34,37,39,42).…”

mentioning

confidence: 99%

NTPDASE4 Gene Products Cooperate with the Adenovirus E4orf4 Protein through PP2A-Dependent and -Independent Mechanisms and Contribute to Induction of Cell Death

Avital-Shacham

Sharf

Kleinberger

2014

J Virol

View full text Add to dashboard Cite

The adenovirus E4orf4 protein induces nonclassical apoptosis in mammalian cells through at least two complementing pathways regulated by the interactions of E4orf4 with protein phosphatase 2A (PP2A) and Src kinases. In Saccharomyces cerevisiae cells, which do not express Src, E4orf4 induces PP2A-dependent toxicity. The yeast Golgi apyrase Ynd1 was found to contribute to E4orf4-mediated toxicity and to interact with the PP2A-B55␣ regulatory subunit. In addition, a mammalian Ynd1 orthologue, the NTPDASE4 gene product Golgi UDPase, was shown to physically interact with E4orf4. Here we report that knockdown of NTPDASE4 suppressed E4orf4-induced cell death. Conversely, overexpression of the NTPDASE4 gene products Golgi UDPase and LALP70 enhanced E4orf4-induced cell killing. We found that similarly to results obtained in yeast, the apyrase activity of mammalian UDPase was not required for its contribution to E4orf4-induced toxicity. The interaction between E4orf4 and UDPase had two consequences: a PP2A-dependent one, resulting in increased UDPase levels, and a PP2A-independent outcome that led to dissociation of large UDPase-containing protein complexes. The present report extends our findings in yeast to E4orf4-mediated death of mammalian cells, and combined with previous results, it suggests that the E4orf4-NTPDase4 pathway, partly in association with PP2A, may provide an alternative mechanism for the E4orf4-Src pathway to contribute to the cytoplasmic death function of E4orf4. IMPORTANCEThe adenovirus E4orf4 protein contributes to regulation of the progression of virus infection from the early to the late phase, and when expressed alone, it induces a unique caspase-independent programmed cell death which is more efficient in cancer cells than in normal cells. The interactions of E4orf4 with cellular proteins that mediate its functions, such as PP2A and Src kinases, are highly conserved in evolution. The results presented here reveal that the NTPDASE4 gene product Golgi UDPase, first discovered to contribute to E4orf4 toxicity in Saccharomyces cerevisiae, associates with E4orf4 and plays a role in induction of cell death in mammalian cells. Details of the functional interaction between E4orf4, PP2A, and the UDPase are described. Identification of the evolutionarily conserved mechanisms underlying E4orf4 activity will increase our understanding of the interactions between the virus and the host cell and will contribute to our grasp of the unique mode of E4orf4-induced cell death.

show abstract

Adenovirus E4 Open Reading Frame 4-Induced Dephosphorylation Inhibits E1A Activation of the E2 Promoter and E2F-1-Mediated Transactivation Independently of the Retinoblastoma Tumor Suppressor Protein

Cited by 33 publications

References 41 publications

Cancer-selective therapy of the future: Apoptin and its mechanism of action

Cancer-selective therapy of the future: Apoptin and its mechanism of action

YND1 Interacts with CDC55 and Is a Novel Mediator of E4orf4-induced Toxicity

NTPDASE4 Gene Products Cooperate with the Adenovirus E4orf4 Protein through PP2A-Dependent and -Independent Mechanisms and Contribute to Induction of Cell Death

Contact Info

Product

Resources

About