Skip to main content

Advertisement

SpringerLink
Log in

Activating transcription factor 4 (ATF4) is upregulated by human herpesvirus 8 infection, increases virus replication and promotes proangiogenic properties

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

Human herpesvirus 8 (HHV-8) triggers proangiogenic behaviour in endothelial cells by inducing monocyte chemoattractant protein 1 (MCP-1) through activation of Nuclear Factor κB (NF-κB). However, NF-κB inhibition still results in partial MCP-1 induction and consequent angiogenesis, suggesting the involvement of another transcriptional pathway. We analysed activating transcription factor 4 (ATF4), since it is central in the cellular response to stress and is involved in angiogenesis. The results show that HHV-8 upregulates ATF4 expression, which in turn promotes HHV-8 infection, and induces MCP-1 production and proangiogenic properties in endothelial cells. By contrast, ATF4 silencing decreases virus replication and inhibits virus-induced MCP-1 production and induction of tube-like structures. Therefore, ATF4 plays a role in HHV-8 replication and associated virus-induced angiogenesis. The elucidation of molecular pathways involved in this process will result in a better understanding of the virus-induced angiogenic process and might help in designing novel therapies to reduce tumour growth.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Ameri K, Lewis CE, Raida M, Sowter H, Hai T, Harris AL (2004) Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells. Blood 103:1876–1882

    Article  PubMed  CAS  Google Scholar 

  2. Ameri K, Harris AL (2008) Activating transcription factor 4. Int J Biochem Cell Biol 40:14–21

    Article  PubMed  CAS  Google Scholar 

  3. Antman K, Chang Y (2000) Kaposi’s sarcoma. N Engl J Med 342:1027–1038

    Article  PubMed  CAS  Google Scholar 

  4. Arvanitakis L, Mesri EA, Nador RG, Said JW, Asch AS, Knowles DM, Cesarman E (1996) Establishment and characterization of a primary effusion (body cavity-based) lymphoma cell line (BC-3) harboring kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) in the absence of Epstein-Barr virus. Blood 88:2648–2654

    PubMed  CAS  Google Scholar 

  5. Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C (2005) ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. Embo J 24:3470–3481

    Article  PubMed  CAS  Google Scholar 

  6. Blais JD, Filipenko V, Bi M, Harding HP, Ron D, Koumenis C, Wouters BG, Bell JC (2004) Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol 24:7469–7482

    Article  PubMed  CAS  Google Scholar 

  7. Boshoff C, Gao SJ, Healy LE, Matthews S, Thomas AJ, Coignet L, Warnke RA, Strauchen JA, Matutes E, Kamel OW, Moore PS, Weiss RA, Chang Y (1998) Establishing a KSHV+ cell line (BCP-1) from peripheral blood and characterizing its growth in Nod/SCID mice. Blood 91:1671–1679

    PubMed  CAS  Google Scholar 

  8. Caselli E, Galvan M, Santoni F, Rotola A, Caruso A, Cassai E, Luca DD (2003) Human herpesvirus-8 (Kaposi’s sarcoma-associated virus) ORF50 increases in vitro cell susceptibility to human immunodeficiency virus type 1 infection. J Gen Virol 84:1123–1131

    Article  PubMed  CAS  Google Scholar 

  9. Caselli E, Galvan M, Cassai E, Caruso A, Sighinolfi L, Di Luca D (2005) Human herpesvirus 8 enhances human immunodeficiency virus replication in acutely infected cells and induces reactivation in latently infected cells. Blood 106:2790–2797

    Article  PubMed  CAS  Google Scholar 

  10. Caselli E, Fiorentini S, Amici C, Di Luca D, Caruso A, Santoro MG (2007) Human herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1-dependent capillary-like structure formation: role of the IKK/NF-kappaB pathway. Blood 109:2718–2726

    PubMed  CAS  Google Scholar 

  11. Caselli E, Galvan M, Santoni F, Alvarez S, de Lera AR, Ivanova D, Gronemeyer H, Caruso A, Guidoboni M, Cassai E, Dolcetti R, Di Luca D (2008) Retinoic acid analogues inhibit human herpesvirus 8 replication. Antivir Ther 13:199–209

    PubMed  CAS  Google Scholar 

  12. Casper C, Nichols WG, Huang ML, Corey L, Wald A (2004) Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood 103:1632–1634

    Article  PubMed  CAS  Google Scholar 

  13. Cesarman E, Moore PS, Rao PH, Inghirami G, Knowles DM, Chang Y (1995) In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi’s sarcoma-associated herpesvirus-like (KSHV) DNA sequences. Blood 86:2708–2714

    PubMed  CAS  Google Scholar 

  14. Chakraborty G, Jain S, Kundu GC (2008) Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms. Cancer Res 68:152–161

    Article  PubMed  CAS  Google Scholar 

  15. Chang YCE, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266:1865–1869

    Article  PubMed  CAS  Google Scholar 

  16. Chen H, Pan YX, Dudenhausen EE, Kilberg MS (2004) Amino acid deprivation induces the transcription rate of the human asparagine synthetase gene through a timed program of expression and promoter binding of nutrient-responsive basic region/leucine zipper transcription factors as well as localized histone acetylation. J Biol Chem 279:50829–50839

    Article  PubMed  CAS  Google Scholar 

  17. Choi YB, Nicholas J (2010) Induction of angiogenic chemokine CCL2 by human herpesvirus 8 chemokine receptor. Virology 397:369–378

    Article  PubMed  CAS  Google Scholar 

  18. Conaldi PG, Serra C, Mossa A, Falcone V, Basolo F, Camussi G, Dolei A, Toniolo A (1997) Persistent infection of human vascular endothelial cells by group B coxsackieviruses. J Infect Dis 175:693–696

    Article  PubMed  CAS  Google Scholar 

  19. Cullinan SB, Diehl JA (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38:317–332

    Article  PubMed  CAS  Google Scholar 

  20. Elbarghati L, Murdoch C, Lewis CE (2008) Effects of hypoxia on transcription factor expression in human monocytes and macrophages. Immunobiology 213:899–908

    Article  PubMed  CAS  Google Scholar 

  21. Fels DR, Koumenis C (2006) The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol Ther 5:723–728

    PubMed  CAS  Google Scholar 

  22. Fonsato V, Buttiglieri S, Deregibus MC, Bussolati B, Caselli E, Di Luca D, Camussi G (2008) PAX2 expression by HHV-8-infected endothelial cells induced a proangiogenic and proinvasive phenotype. Blood 111:2806–2815

    Article  PubMed  CAS  Google Scholar 

  23. Gargalovic PS, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Baruch-Oren T, Berliner JA, Kirchgessner TG, Lusis AJ (2006) The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol 26:2490–2496

    Article  PubMed  CAS  Google Scholar 

  24. Granberg F, Svensson C, Pettersson U, Zhao H (2006) Adenovirus-induced alterations in host cell gene expression prior to the onset of viral gene expression. Virology 353:1–5

    Article  PubMed  CAS  Google Scholar 

  25. Grayson W, Pantanowitz L (2008) Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol 3:31

    Article  PubMed  Google Scholar 

  26. Hai T, Curran T (1991) Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci USA 88:3720–3724

    Article  PubMed  CAS  Google Scholar 

  27. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108

    Article  PubMed  CAS  Google Scholar 

  28. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633

    Article  PubMed  CAS  Google Scholar 

  29. Hayward GS (2003) Initiation of angiogenic Kaposi’s sarcoma lesions. Cancer Cell 3:1–3

    Article  PubMed  CAS  Google Scholar 

  30. Isler JA, Skalet AH, Alwine JC (2005) Human cytomegalovirus infection activates and regulates the unfolded protein response. J Virol 79:6890–6899

    Article  PubMed  CAS  Google Scholar 

  31. Jordan R, Wang L, Graczyk TM, Block TM, Romano PR (2002) Replication of a cytopathic strain of bovine viral diarrhea virus activates PERK and induces endoplasmic reticulum stress-mediated apoptosis of MDBK cells. J Virol 76:9588–9599

    Article  PubMed  CAS  Google Scholar 

  32. Koumenis C (2006) ER stress, hypoxia tolerance and tumor progression. Curr Mol Med 6:55–69

    Article  PubMed  CAS  Google Scholar 

  33. Kozutsumi Y, Segal M, Normington K, Gething MJ, Sambrook J (1988) The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332:462–464

    Article  PubMed  CAS  Google Scholar 

  34. Li X, Feng J, Sun R (2011) Oxidative stress induces reactivation of Kaposi’s sarcoma-associated herpesvirus and death of primary effusion lymphoma cells. J Virol 85:715–724

    Article  PubMed  CAS  Google Scholar 

  35. Liang G, Hai T (1997) Characterization of human activating transcription factor 4, a transcriptional activator that interacts with multiple domains of cAMP-responsive element-binding protein (CREB)-binding protein. J Biol Chem 272:24088–24095

    Article  PubMed  CAS  Google Scholar 

  36. Lim C, Sohn H, Gwack Y, Choe J (2000) Latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity. J Gen Virol 81:2645–2652

    PubMed  CAS  Google Scholar 

  37. Ma Q, Cavallin LE, Yan B, Zhu S, Duran EM, Wang H, Hale LP, Dong C, Cesarman E, Mesri EA, Goldschmidt-Clermont PJ (2009) Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi’s sarcoma. Proc Natl Acad Sci 106:8683–8688

    Article  PubMed  CAS  Google Scholar 

  38. Malabanan KP, Khachigian LM (2010) Activation transcription factor-4 and the acute vascular response to injury. J Mol Med 88:545–552

    Article  PubMed  CAS  Google Scholar 

  39. Mesri EA, Cesarman E, Boshoff C (2010) Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer 10:707–719

    Article  PubMed  CAS  Google Scholar 

  40. Oskolkova OV, Afonyushkin T, Leitner A, von Schlieffen E, Gargalovic PS, Lusis AJ, Binder BR, Bochkov VN (2008) ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response. Blood 112:330–339

    Article  PubMed  CAS  Google Scholar 

  41. Pereira ER, Liao N, Neale GA, Hendershot LM (2010) Transcriptional and post-transcriptional regulation of proangiogenic factors by the unfolded protein response. PLoS One 5. pii: e12521

  42. Renne R, Zhong W, Herndier B, McGrath M, Abbey N, Kedes D, Ganem D (1996) Lytic growth of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med 2:342–346

    Article  PubMed  CAS  Google Scholar 

  43. Santoni F, Lindner I, Caselli E, Goltz M, Di Luca D, Ehlers B (2006) Molecular interactions between porcine and human gammaherpesviruses: implications for xenografts? Xenotransplantation 13:308–317

    Article  PubMed  Google Scholar 

  44. Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, d’Agay MF, Clauvel JP, Raphael M, Degos L et al (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood 86:1276–1280

    PubMed  CAS  Google Scholar 

  45. Staskus KA, Zhong W, Gebhard K, Herndier B, Wang H, Renne R, Beneke J, Pudney J, Anderson DJ, Ganem D, Haase AT (1997) Kaposi’s sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 71:715–719

    PubMed  CAS  Google Scholar 

  46. Sturzl M, Wunderlich A, Ascherl G, Hohenadl C, Monini P, Zietz C, Browning PJ, Neipel F, Biberfeld P, Ensoli B (1999) Human herpesvirus-8 (HHV-8) gene expression in Kaposi’s sarcoma (KS) primary lesions: an in situ hybridization study. Leukemia 13(Suppl 1):S110–S112

    Article  PubMed  Google Scholar 

  47. Su HL, Liao CL, Lin YL (2002) Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response. J Virol 76:4162–4171

    Article  PubMed  CAS  Google Scholar 

  48. Sullivan R, Dezube BJ, Koon HB (2006) Signal transduction targets in Kaposi’s sarcoma. Curr Opin Oncol 18:456–462

    Article  PubMed  CAS  Google Scholar 

  49. Tardif KD, Mori K, Siddiqui A (2002) Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J Virol 76:7453–7459

    Article  PubMed  CAS  Google Scholar 

  50. Ye F, Zhou F, Bedolla RG, Jones T, Lei X, Kang T, Guadalupe M, Gao S-J (2011) Reactive oxygen species hydrogen peroxide mediates Kaposi’s sarcoma-associated herpesvirus reactivation from latency. PLoS Pathog 7:e1002054

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Italian Ministry of University and Scientific Research (PRIN projects), FAR (University of Ferrara) and Istituto Superiore di Sanità (ISS; AIDS project). We thank Dr. T. Hai (Department of Molecular and Cellular Biochemistry, Neurobiotechnology Center, Ohio State University, Columbus, USA) for providing the pCG-ATF4 plasmid. We thank Annalisa Peverati for excellent technical assistance, and Linda M. Sartor for revising the English manuscript

Conflict of interest

The authors declare that they have no conflicting interests.

Author information

Authors and Affiliations

  1. Section of Microbiology, Department of Experimental and Diagnostic Medicine, University of Ferrara, via L. Borsari 46, 44100, Ferrara, Italy

    Elisabetta Caselli, Sabrina Benedetti, Jessica Grigolato & Dario Di Luca

  2. Section of Microbiology, University of Brescia, Brescia, Italy

    Arnaldo Caruso

Authors
  1. Elisabetta Caselli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabrina Benedetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jessica Grigolato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arnaldo Caruso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dario Di Luca
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elisabetta Caselli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Caselli, E., Benedetti, S., Grigolato, J. et al. Activating transcription factor 4 (ATF4) is upregulated by human herpesvirus 8 infection, increases virus replication and promotes proangiogenic properties. Arch Virol 157, 63–74 (2012). https://doi.org/10.1007/s00705-011-1144-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-011-1144-3

Keywords

Search

Navigation