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Infection with E1B-mutant adenovirus stabilizes p53 but blocks p53 acetylation and activity through E1A

Oncogene volume 30, pages 865–875 (2011)Cite this article

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Abstract

Wild-type adenovirus type 5 eliminates p53 through the E1B-55kDa and E4-34kDa gene products. Deletion or mutation of E1B-55kDa has long been thought to confer p53-selective replication of oncolytic viruses. We show here that infection with E1B-defective adenovirus mutants induces massive accumulation of p53, without obvious defects in p53 localization, phosphorylation, conformation and oligomerization. Nonetheless, p53 completely failed to induce its target genes in this scenario, for example, p21/CDKN1A, Mdm2 and PUMA. Two regions of the E1A gene products independently contributed to the suppression of p21 transcription. Depending on the E1A conserved region 3, E1B-defective adenovirus impaired the ability of the transcription factor Sp1 to bind the p21 promoter. Moreover, the amino terminal region of E1A, binding the acetyl transferases p300 and CREB-binding protein, blocked p53 K382 acetylation in infected cells. Mutating either of these E1A regions, in addition to E1B, partially restored p21 mRNA levels. Our findings argue that adenovirus attenuates p53-mediated p21 induction, through at least two E1B-independent mechanisms. Other virus species and cancer cells may employ analogous strategies to impair p53 activity.

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References

  • Atz J, Wagner P, Roemer K . (2000). Function, oligomerization, and conformation of tumor-associated p53 proteins with mutated C-terminus. J Cell Biochem 76: 572–584.

    Article  CAS  Google Scholar 

  • Avantaggiati ML, Ogryzko V, Gardner K, Giordano A, Levine AS, Kelly K . (1997). Recruitment of p300/CBP in p53-dependent signal pathways. Cell 89: 1175–1184.

    Article  CAS  Google Scholar 

  • Beckerman R, Donner AJ, Mattia M, Peart MJ, Manley JL, Espinosa JM et al. (2009). A role for Chk1 in blocking transcriptional elongation of p21 RNA during the S-phase checkpoint. Genes Dev 23: 1364–1377.

    Article  CAS  Google Scholar 

  • Bernat A, Avvakumov N, Mymryk JS, Banks L . (2003). Interaction between the HPV E7 oncoprotein and the transcriptional coactivator p300. Oncogene 22: 7871–7881.

    Article  Google Scholar 

  • Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M et al. (1996). An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274: 373–376.

    Article  CAS  Google Scholar 

  • Bode AM, Dong Z . (2004). Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4: 793–805.

    Article  CAS  Google Scholar 

  • Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC et al. (2004). A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119: 591–602.

    Article  CAS  Google Scholar 

  • Braun CJ, Zhang X, Savelyeva I, Wolff S, Moll UM, Schepeler T et al. (2008). p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest. Cancer Res 68: 10094–10104.

    Article  CAS  Google Scholar 

  • Bridge E, Ketner G . (1990). Interaction of adenoviral E4 and E1b products in late gene expression. Virology 174: 345–353.

    Article  CAS  Google Scholar 

  • Carlock LR, Jones NC . (1981). Transformation-defective mutant of adenovirus type 5 containing a single altered E1a mRNA species. J Virol 40: 657–664.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Debbas M, White E . (1993). Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev 7: 546–554.

    Article  CAS  Google Scholar 

  • Dobner T, Horikoshi N, Rubenwolf S, Shenk T . (1996). Blockage by adenovirus E4orf6 of transcriptional activation by the p53 tumor suppressor. Science 272: 1470–1473.

    Article  CAS  Google Scholar 

  • Faiola F, Liu X, Lo S, Pan S, Zhang K, Lymar E et al. (2005). Dual regulation of c-Myc by p300 via acetylation-dependent control of Myc protein turnover and coactivation of Myc-induced transcription. Mol Cell Biol 25: 10220–10234.

    Article  CAS  Google Scholar 

  • Ferrari R, Pellegrini M, Horwitz GA, Xie W, Berk AJ, Kurdistani SK . (2008). Epigenetic reprogramming by adenovirus e1a. Science 321: 1086–1088.

    Article  CAS  Google Scholar 

  • Ferreon JC, Martinez-Yamout MA, Dyson HJ, Wright PE . (2009). Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein. Proc Natl Acad Sci USA 106: 13260–13265.

    Article  CAS  Google Scholar 

  • Gartel AL, Ye X, Goufman E, Shianov P, Hay N, Najmabadi F et al. (2001). Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Proc Natl Acad Sci USA 98: 4510–4515.

    Article  CAS  Google Scholar 

  • Goodrum FD, Ornelles DA . (1998). p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection. J Virol 72: 9479–9490.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gottifredi V, Shieh S, Taya Y, Prives C . (2001). p53 accumulates but is functionally impaired when DNA synthesis is blocked. Proc Natl Acad Sci USA 98: 1036–1041.

    Article  CAS  Google Scholar 

  • Harada H, Nakagawa H, Oyama K, Takaoka M, Andl CD, Jacobmeier B et al. (2003). Telomerase induces immortalization of human esophageal keratinocytes without p16INK4a inactivation. Mol Cancer Res 1: 729–738.

    CAS  PubMed  Google Scholar 

  • Harlow E, Whyte P, Franza Jr BR, Schley C . (1986). Association of adenovirus early-region 1A proteins with cellular polypeptides. Mol Cell Biol 6: 1579–1589.

    Article  CAS  Google Scholar 

  • Harrod R, Nacsa J, Van Lint C, Hansen J, Karpova T, McNally J et al. (2003). Human immunodeficiency virus type-1 Tat/co-activator acetyltransferase interactions inhibit p53Lys-320 acetylation and p53-responsive transcription. J Biol Chem 278: 12310–12318.

    Article  CAS  Google Scholar 

  • Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH . (1997). ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med 3: 639–645.

    Article  CAS  Google Scholar 

  • Hobom U, Dobbelstein M . (2004). E1B-55-kilodalton protein is not required to block p53-induced transcription during adenovirus infection. J Virol 78: 7685–7697.

    Article  CAS  Google Scholar 

  • Hsu CH, Chang MD, Tai KY, Yang YT, Wang PS, Chen CJ et al. (2004). HCMV IE2-mediated inhibition of HAT activity downregulates p53 function. Embo J 23: 2269–2280.

    Article  CAS  Google Scholar 

  • Ito A, Lai CH, Zhao X, Saito S, Hamilton MH, Appella E et al. (2001). p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. Embo J 20: 1331–1340.

    Article  CAS  Google Scholar 

  • Iyer NG, Ozdag H, Caldas C . (2004). p300/CBP and cancer. Oncogene 23: 4225–4231.

    Article  CAS  Google Scholar 

  • Jones N, Shenk T . (1979). Isolation of adenovirus type 5 host range deletion mutants defective for transformation of rat embryo cells. Cell 17: 683–689.

    Article  CAS  Google Scholar 

  • Koch P, Gatfield J, Lober C, Hobom U, Lenz-Stoppler C, Roth J et al. (2001). Efficient replication of adenovirus despite the overexpression of active and nondegradable p53. Cancer Res 61: 5941–5947.

    CAS  PubMed  Google Scholar 

  • Koutsodontis G, Vasilaki E, Chou WC, Papakosta P, Kardassis D . (2005). Physical and functional interactions between members of the tumour suppressor p53 and the Sp families of transcription factors: importance for the regulation of genes involved in cell-cycle arrest and apoptosis. Biochem J 389: 443–455.

    Article  CAS  Google Scholar 

  • Lagger G, Doetzlhofer A, Schuettengruber B, Haidweger E, Simboeck E, Tischler J et al. (2003). The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene. Mol Cell Biol 23: 2669–2679.

    Article  CAS  Google Scholar 

  • Levine AJ . (2009). The common mechanisms of transformation by the small DNA tumor viruses: The inactivation of tumor suppressor gene products: p53. Virology 384: 285–293.

    Article  CAS  Google Scholar 

  • Lill NL, Grossman SR, Ginsberg D, DeCaprio J, Livingston DM . (1997). Binding and modulation of p53 by p300/CBP coactivators. Nature 387: 823–827.

    Article  CAS  Google Scholar 

  • Liu F, Green MR . (1994). Promoter targeting by adenovirus E1a through interaction with different cellular DNA-binding domains. Nature 368: 520–525.

    Article  CAS  Google Scholar 

  • Lowe SW, Ruley HE . (1993). Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev 7: 535–545.

    Article  CAS  Google Scholar 

  • O'Shea CC, Johnson L, Bagus B, Choi S, Nicholas C, Shen A et al. (2004). Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 6: 611–623.

    Article  CAS  Google Scholar 

  • O'Shea CC, Soria C, Bagus B, McCormick F . (2005). Heat shock phenocopies E1B-55 K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy. Cancer Cell 8: 61–74.

    Article  CAS  Google Scholar 

  • Pilder S, Moore M, Logan J, Shenk T . (1986). The adenovirus E1B-55 K transforming polypeptide modulates transport or cytoplasmic stabilization of viral and host cell mRNAs. Mol Cell Biol 6: 470–476.

    Article  CAS  Google Scholar 

  • Ray R, Snyder RC, Thomas S, Koller CA, Miller DM . (1989). Mithramycin blocks protein binding and function of the SV40 early promoter. J Clin Invest 83: 2003–2007.

    Article  CAS  Google Scholar 

  • Rothmann T, Hengstermann A, Whitaker NJ, Scheffner M, zur Hausen H . (1998). Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells. J Virol 72: 9470–9478.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shen Y, Kitzes G, Nye JA, Fattaey A, Hermiston T . (2001). Analyses of single-amino-acid substitution mutants of adenovirus type 5 E1B-55K protein. J Virol 75: 4297–4307.

    Article  CAS  Google Scholar 

  • Shepherd SE, Howe JA, Mymryk JS, Bayley ST . (1993). Induction of the cell cycle in baby rat kidney cells by adenovirus type 5 E1A in the absence of E1B and a possible influence of p53. J Virol 67: 2944–2949.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Steegenga WT, van Laar T, Riteco N, Mandarino A, Shvarts A, van der Eb AJ et al. (1996). Adenovirus E1A proteins inhibit activation of transcription by p53. Mol Cell Biol 16: 2101–2109.

    Article  CAS  Google Scholar 

  • Thornborrow EC, Manfredi JJ . (2001). The tumor suppressor protein p53 requires a cofactor to activate transcriptionally the human BAX promoter. J Biol Chem 276: 15598–15608.

    Article  CAS  Google Scholar 

  • Turnell AS, Grand RJ, Gallimore PH . (1999). The replicative capacities of large E1B-null group A and group C adenoviruses are independent of host cell p53 status. J Virol 73: 2074–2083.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Turnell AS, Grand RJ, Gorbea C, Zhang X, Wang W, Mymryk JS et al. (2000). Regulation of the 26S proteasome by adenovirus E1A. Embo J 19: 4759–4773.

    Article  CAS  Google Scholar 

  • Wang X, Wang J, Lin S, Geng Y, Wang J, Jiang B . (2008). Sp1 is involved in H2O2-induced PUMA gene expression and apoptosis in colorectal cancer cells. J Exp Clin Cancer Res 27: 44.

    Article  Google Scholar 

  • Weigel S, Dobbelstein M . (2000). The nuclear export signal within the E4orf6 protein of adenovirus type 5 supports virus replication and cytoplasmic accumulation of viral mRNA. J Virol 74: 764–772.

    Article  CAS  Google Scholar 

  • Wong K, Sharma A, Awasthi S, Matlock EF, Rogers L, Van Lint C et al. (2005). HIV-1 Tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin signaling through CREB. J Biol Chem 280: 9390–9399.

    Article  CAS  Google Scholar 

  • Zhao Y, Lu S, Wu L, Chai G, Wang H, Chen Y et al. (2006). Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Mol Cell Biol 26: 2782–2790.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank JS Mymryk, RJA Grand, X Zhang and G Ketner for viruses, K Roemer for plasmids, AJ Levine for antibodies, OG Opitz for cells, C Hippel and A Dickmanns for excellent technical assistance, and S Johnsen for the help with ChIP experiments. The work was supported by the German Cancer Aid/Dr Mildred Scheel Stiftung, the EU 6th Framework Program (Integrated Project Active p53), the German Research Foundation (DFG), the Wilhelm Sander Stiftung, the Statens Sundhedsvidenskabelige Forskningsråd of Denmark, the Danish Cancer Society, and the Novonordisk fonden.

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  1. Department of Molecular Oncology, Göttingen Center of Molecular Biosciences, Ernst Caspari Haus, University of Göttingen, Göttingen, Germany

    I Savelyeva & M Dobbelstein

  2. Medical Biotechnology Center, Institute for Medical Biology, University of Southern Denmark, Odense C, Denmark

    I Savelyeva & M Dobbelstein

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  1. I Savelyeva
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Correspondence to M Dobbelstein.

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Savelyeva, I., Dobbelstein, M. Infection with E1B-mutant adenovirus stabilizes p53 but blocks p53 acetylation and activity through E1A. Oncogene 30, 865–875 (2011). https://doi.org/10.1038/onc.2010.461

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