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Clinical and Translational Oncology

, Volume 16, Issue 3, pp 293–300 | Cite as

HIV-1 viral protein R downregulates Ebp1 and stabilizes p53 in glioblastoma U87MG cells

  • S. Zhang
  • B. ZhangEmail author
  • X. Xu
  • L. Wang
  • X. Feng
  • Q. Wang
  • H. Huang
  • J. Wu
  • P. Li
  • J. WangEmail author
Research Article

Abstract

Purpose

HIV-1 viral protein R (Vpr) inhibits cell growth and induces apoptosis in a wide range of cancers. However, the mechanism by which Vpr induces cell cycle arrest and apoptosis in GBM cell lines is unclear. The present work was taken to detect the proteins interacted with Vpr in U87MG cells.

Methods

We analyzed the differential expression of proteins between glioblastoma cell U87MG treated with Ad-Vpr and untreated by 2-DE. We used antibody array analysis to analyze the common molecules in the apoptosis of U87MG induced by Vpr.

Results

We analyzed the differential expression of proteins between U87MG cell treated with Ad-Vpr and untreated, and found that proteins related to DNA damage repair or different apoptosis pathways were involved in the G2 arrest and apoptosis mediated by Vpr. In addition, proliferation-associated protein 2G4 (PA2G4), also known as Ebp1, was down-regulated and p53 was up-regulated in U87MG cells treated with Ad-Vpr.

Conclusions

Our data suggest that Vpr may inhibit Ebp1 to stabilize p53, which in turn leads to G2 arrest and apoptosis in U87MG cells.

Keywords

Vpr Proteome Apoptosis Cell cycle arrest p53 Ebp1 

Notes

Acknowledgments

This work was supported by Tianjin Science and Technology Committee (11JCYBJC12100, 12ZDZSY17700), the National Natural Science Foundation of China (81101911), Tianjin Health Bureau Science and Technique Foundation (11KG115), and State Key Clinical Department of Neurosurgery.

Conflict of interest

There are no conflicts of interest.

References

  1. 1.
    Andersen JL, Le Rouzic E, Planelles V. HIV-1 Vpr: mechanisms of G2 arrest and apoptosis. Exp Mol Pathol. 2008;85:2–10.Google Scholar
  2. 2.
    Langevin C, Maidou-Peindara P, Aas PA, Jacquot G, Otterlei M, Slupphaug G, et al. Human immunodeficiency virus type 1 Vpr modulates cellular expression of UNG2 via a negative transcriptional effect. J Virol. 2009;83:10256–63.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Withers-Ward ES, Mueller TD, Chen IS, Feigon J. Biochemical and structural analysis of the interaction between the UBA(2) domain of the DNA repair protein HHR23A and HIV-1 Vpr. Biochemistry-Us. 2000;39:14103–12.Google Scholar
  4. 4.
    Planelles V, Benichou S. Vpr and its interactions with cellular proteins. Curr Top Microbiol Immunol. 2009;339:177–200.Google Scholar
  5. 5.
    Zhang B, Feng X, Wang J, Xu X, Lin N, Liu H. Combined antitumor effect of Ad-bFGF-siRNA and Ad-Vpr on the growth of xenograft glioma in nude mouse model. Pathol Oncol Res. 2011;17:237–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Nakai-Murakami C, Minemoto Y, Ishizaka Y. Vpr-induced DNA double-strand breaks: molecular mechanism and biological relevance. Curr HIV Res. 2009;7:109–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Nakai-Murakami C, Shimura M, Kinomoto M, Takizawa Y, Tokunaga K, Taguchi T, et al. HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination. Oncogene. 2007;26:477–86.PubMedCrossRefGoogle Scholar
  8. 8.
    Tachiwana H, Shimura M, Nakai-Murakami C, Tokunaga K, Takizawa Y, Sata T, et al. HIV-1 Vpr induces DNA double-strand breaks. Cancer Res. 2006;66:627–31.PubMedCrossRefGoogle Scholar
  9. 9.
    Lai M, Zimmerman ES, Planelles V, Chen J. Activation of the ATR pathway by human immunodeficiency virus type 1 Vpr involves its direct binding to chromatin in vivo. J Virol. 2005;79:15443–51.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Harrison JC, Haber JE. Surviving the breakup: the DNA damage checkpoint. Annu Rev Genet. 2006;40:209–35.Google Scholar
  11. 11.
    Capanni C, Cenni V, Haraguchi T, Squarzoni S, Schuchner S, Ogris E, et al. Lamin A precursor induces barrier-to-autointegration factor nuclear localization. Cell Cycle. 2010;9:2600–10.Google Scholar
  12. 12.
    Peter A, Reimer S. Evolution of the lamin protein family: what introns can tell. Nucleus. 2012;3:44–59.PubMedCrossRefGoogle Scholar
  13. 13.
    Watanabe N, Yamaguchi T, Akimoto Y, Rattner JB, Hirano H, Nakauchi H. Induction of M-phase arrest and apoptosis after HIV-1 Vpr expression through uncoupling of nuclear and centrosomal cycle in HeLa cells. Exp Cell Res. 2000;258:261–9.Google Scholar
  14. 14.
    Moon HS, Yang JS. Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells. Mol Cells. 2006;21:7–20.Google Scholar
  15. 15.
    Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–19.PubMedCrossRefGoogle Scholar
  16. 16.
    Ma B, Zhang H, Wang J, Zhang B, Xu X, Cheng B. HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells. Oncol Rep. 2012;28:358–64.PubMedGoogle Scholar
  17. 17.
    Muthumani K, Hwang DS, Desai BM, Zhang D, Dayes N, Green DR, et al. HIV-1 Vpr induces apoptosis through caspase 9 in T cells and peripheral blood mononuclear cells. J Biol Chem. 2002;277:37820–31.Google Scholar
  18. 18.
    Snyder A, Alsauskas ZC, Leventhal JS, Rosenstiel PE, Gong P, Chan JJ, et al. HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells. Aids. 2010;24:1107–19.Google Scholar
  19. 19.
    Snyder A, Ross MJ. Murine models of Vpr-mediated pathogenesis. Curr HIV Res. 2009;7:129–35.PubMedCrossRefGoogle Scholar
  20. 20.
    Yoo JY, Wang XW, Rishi AK, Lessor T, Xia XM, Gustafson TA, et al. Interaction of the PA2G4 (EBP1) protein with ErbB-3 and regulation of this binding by heregulin. Br J Cancer. 2000;82:683–90.Google Scholar
  21. 21.
    Liu Z, Ahn JY, Liu X, Ye K. Ebp1 isoforms distinctively regulate cell survival and differentiation. Proc Natl Acad Sci USA. 2006;103:10917–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Kim CK, Nguyen TL, Joo KM, Nam DH, Park J, Lee KH, et al. Negative regulation of p53 by the long isoform of ErbB3 binding protein Ebp1 in brain tumors. Cancer Res. 2010;70:9730–41.Google Scholar
  23. 23.
    Liu Z, Oh SM, Okada M, Liu X, Cheng D, Peng J, et al. Human BRE1 is an E3 ubiquitin ligase for Ebp1 tumor suppressor. Mol Biol Cell. 2009;20:757–68.Google Scholar
  24. 24.
    Amini S, Saunders M, Kelley K, Khalili K, Sawaya BE. Interplay between HIV-1 Vpr and Sp1 modulates p21(WAF1) gene expression in human astrocytes. J Biol Chem. 2004;279:46046–56.PubMedCrossRefGoogle Scholar
  25. 25.
    Chowdhury IH, Wang XF, Landau NR, Robb ML, Polonis VR, Birx DL, et al. HIV-1 Vpr activates cell cycle inhibitor p21/Waf1/Cip1: a potential mechanism of G2/M cell cycle arrest. Virology. 2003;305:371–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Muthumani K, Zhang D, Hwang DS, Kudchodkar S, Dayes NS, Desai BM, et al. Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. Oncogene. 2002;21:4613–25.PubMedCrossRefGoogle Scholar
  27. 27.
    Kim CK, Lee SB, Nguyen TL, Lee KH, Um SH, Kim J, et al. Long isoform of ErbB3 binding protein, p48, mediates protein kinase B/Akt-dependent HDM2 stabilization and nuclear localization. Exp Cell Res. 2012;318:136–43.PubMedCrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2013

Authors and Affiliations

  1. 1.Tianjin Neurosurgical InstituteTianjin Huanhu HospitalTianjinPeople’s Republic of China
  2. 2.Clinical Lab of Tianjin Huanhu HospitalTianjinPeople’s Republic of China
  3. 3.Key Lab for Critical Care Medicine of the Ministry of HealthTianjin First Center HospitalTianjinPeople’s Republic of China

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