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Induction of apoptosis by adenovirus E4orf4 protein

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Abstract

Adenovirus E4orf4 protein is a multifunctional viral regulator that induces p53-independent apoptosis in transformed cells, but not in normal cells. E4orf4-induced apoptosis can occur without activation of known caspases, although E4orf4 induces caspase activity in some cell lines. The interaction of E4orf4 with a specific subpopulation of protein phosphatase 2A (PP2A) molecules that contain B subunits, but not with those that contain B′ subunits, is required for induction of apoptosis. This review suggests the potential use of E4orf4 in cancer therapy, and discusses whether E4orf4-induced apoptosis plays a role in the viral life cycle. Future research directions are also highlighted.

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References

  1. Engel DA, Hardy S, Shenk T. cAMP acts in synergy with E1A protein to activate transcription of the adenovirus early genes E4 and E1A. Genes Dev 1988; 2: 1517–1528.

    PubMed  Google Scholar 

  2. Müller U, Roberts MP, Engel DA, Doerfler W, Shenk T. Induction of transcription factor AP-1 by adenovirus E1A protein and cAMP. Genes Dev 1989; 3: 1991–2002.

    PubMed  Google Scholar 

  3. Müller U, Kleinberger T, Shenk T. Adenovirus E4orf4 protein reduces phosphorylation of c-fos and E1A proteins while simultaneously reducing the level of AP-1. J Virol 1992; 66: 5867–5878.

    PubMed  Google Scholar 

  4. Bondesson M, Ohman K, Mannervik M, Fan S, Akusjarvi G. Adenovirus E4 open reading 4 protein autoregulates E4 transcription by inhibiting E1A transactivation of the E4 promoter. J Virol 1996; 70: 3844–3851.

    PubMed  Google Scholar 

  5. Whalen SG, Marcellus RC, Whalen A, Ahn NG, Ricciardi RP, Branton, PE. Phosphorylation within the transactivation domain of adenovirus E1A protein by mitogen-activated protein kinase regulates expression of early region 4. J Virol 1997; 71: 3545–3553.

    PubMed  Google Scholar 

  6. Mannervik M, Fan S, Strom AC, Helin K, Akusjarvi G. 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. Virology 1999; 256: 313–321.

    PubMed  Google Scholar 

  7. Kanopka A, Muhlemann O, Petersen-Mahrt S, Estmer C, Ohrmalm C, Akusjarvi G. Regulation of adenovirus alternativeRNAsplicing by dephosphorylation of SR proteins. Nature 1998; 393: 185–187.

    PubMed  Google Scholar 

  8. Hulbert DN, Cutt JR, Shenk T. Adenovirus early region 4 encodes functions required for efficient DNA replication, late gene expression, and host cell shutoff. J Virol 1985; 56: 250–257.

    PubMed  Google Scholar 

  9. Kleinberger T, Shenk T. Adenovirus E4orf4 protein binds to protein phosphatase 2A, and the complex down regulates E1Aenhanced junB transcription. J Virol 1993; 67: 7556–7560.

    PubMed  Google Scholar 

  10. Mumby MC, Walter G. Protein serine/threonine phosphatases: structure, regulation, and functions in cell growth. Physiological Reviews 1993; 73: 673–699.

    PubMed  Google Scholar 

  11. Wera S, Hemmings BA. Serine/threonine protein phosphatases. Biochem J 1995; 311: 17–29.

    PubMed  Google Scholar 

  12. Kamibayashi C, Estes R, Lickteig RL, Yang S-I, Craft C, Mumby M. Comparison of heterotrimeric protein phosphatase 2A containing different B subunits. J Biol Chem 1994; 269: 20139–20148.

    PubMed  Google Scholar 

  13. McCright B, Virshup DM. Identification of a new family of protein phosphatase 2A regulatory subunits. J Biol Chem 1995; 270: 26123–26128.

    PubMed  Google Scholar 

  14. Csortos C, Zolnierowicz S, Bako E, Durbin SD, DePaoli-Roach AA. High complexity in the expression of the B0 subunit of protein phosphatase 2A0. J Biol Chem 1996; 271: 2578–2588.

    PubMed  Google Scholar 

  15. Mumby M. Regulation by tumor antigens defines a role for PP2A in signal transduction. Semin Cancer Biol 1995; 6: 229–237.

    PubMed  Google Scholar 

  16. Shtrichman R, Sharf R, Kleinberger T, Adenovirus E4orf4 protein interacts with both B® and B0 subunits of protein phosphatase 2A, but E4orf4-induced apoptosis is mediated only by the interaction with B®. Oncogene 2000; in press.

  17. Shtrichman R, Kleinberger T. Adenovirus type 5 E4 open reading frame 4 protein induces apoptosis in transformed cells. J Virol 1998; 72: 2975–2982.

    PubMed  Google Scholar 

  18. Lavoie JN, Nguyen M, Marcellus RC, Branton PE, Shore GC. E4orf4, a novel adenovirus death factor that induces p53-independent apoptosis by a pathway that is not inhibited by zVAD-fmk. J Cell Biol 1998; 140: 637–645.

    PubMed  Google Scholar 

  19. Marcellus RC, Lavoie JN, Boivin D, Shore GC, Ketner G, Branton PE. The early region 4 orf4 protein of human adenovirus type 5 induces p53-independent cell death by apoptosis. J Virol 1998; 72: 7144–7153.

    PubMed  Google Scholar 

  20. Cryns V, Yuan J. Proteases to die for. Genes and Dev 1998; 12: 1551–1570.

    PubMed  Google Scholar 

  21. Xiang J, Chao DT, Korsmeyer SJ. BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc Natl Acad Sci USA 1996; 93: 14559–14563.

    PubMed  Google Scholar 

  22. Shtrichman R, Sharf R, Barr H, Dobner T, Kleinberger T. Induction of apoptosis by adenovirus E4orf4 protein is specific to transformed cells and requires an interaction with protein phosphatase 2A. Proc Natl Acad Sci USA 1999; 96: 10080–10085.

    PubMed  Google Scholar 

  23. Anderson P. Kinase cascades regulating entry into apoptosis. Microbiol Mol Biol Rev 1997; 61: 33–46.

    PubMed  Google Scholar 

  24. Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three Akts. Genes Dev 1999; 13: 2905–2927.

    PubMed  Google Scholar 

  25. Yamamoto K, Ichijo H, Korsmeyer SJ. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol. Cell Biol 1999; 19: 8469–8478.

    Google Scholar 

  26. Ito T, Deng X, Carr B, May WS. Bcl-2 phosphorylation required for anti-apoptotic function. J Biol Chem 1997; 272: 11671–11673.

    PubMed  Google Scholar 

  27. Gjertsen BT, Doskeland SO. Protein phosphorylation in apoptosis. Biochim Biophys Acta 1995; 1269: 187–199.

    PubMed  Google Scholar 

  28. Yan Y, Shay JW, Wright WE, Mumby MC. Inhibition of protein phosphatase activity induces p53-dependent apoptosis in the absence of p53 transactivation. J Biol Chem 1997; 272: 15220–15226.

    PubMed  Google Scholar 

  29. Song Q, Lavin M. Calyculin A, a potent inhibitor of phosphatases-1 and-2A, prevents apoptosis. Biochem Biophys Res Commun 1993; 190: 47–55.

    PubMed  Google Scholar 

  30. Morana SJ, Wolf CM, Reynolds JE, Brown MK, Eastman A. The involvement of protein phosphatases in the activation of ICE/CED-3 protease, intracellular acidification, DNA digestion, and apoptosis. J Biol Chem 1996; 271: 18263–18271.

    PubMed  Google Scholar 

  31. Santoro MF, Annand RR, Robertson MM, et al. Regulation of protein phosphatase 2A activity by caspase-3 during apoptosis. J Biol Chem 1998; 273: 13119–13128.

    PubMed  Google Scholar 

  32. Deng X, Ito T, Carr B, Mumby M, May WS. Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J Biol Chem 1998; 273: 34157–34163.

    PubMed  Google Scholar 

  33. Matsuyama S, Xu Q, Velours J, Reed JC. The mitochondrial F0F1-ATPase proton pump is required for function of the proapoptotic protein Bax in yeast and mammalian cells. Mol Cell 1998; 1: 327–336.

    PubMed  Google Scholar 

  34. Xu Q, Reed JC. Bax inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol Cell1998; 1: 337–346.

    PubMed  Google Scholar 

  35. Fearnhead HO, Rodriguez J, Govek EE, et al. Oncogenedependent apoptosis is mediated by caspase-9. Proc Natl Acad Sci USA 1998; 95: 13664–13669.

    PubMed  Google Scholar 

  36. White E, Cipriani R, Sabbatini P, Denton A. The adenovirus E1B 19-Kilodalton protein overcomes the cytotoxicity of E1A proteins. J Virol 1991; 65: 2968–2978.

    PubMed  Google Scholar 

  37. Roulston A, Marcellus RC, Branton PE. Viruses and apoptosis. Annu Rev Microbiol 1999; 53: 577–628.

    PubMed  Google Scholar 

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  1. The Gonda Center of Molecular Microbiology, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, 31096, Israel

    T. Kleinberger

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Kleinberger, T. Induction of apoptosis by adenovirus E4orf4 protein. Apoptosis 5, 211–215 (2000). https://doi.org/10.1023/A:1009644210581

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