c-FLIPL regulates PKC via AP-2 to inhibit Bax-mediated apoptosis induced by HIV-1 gp120 in Jurkat cells



c-FLIPL, an inhibitor of caspase 8, is known to inhibit the Fas/caspase 8 apoptotic pathway; however, its involvement of Bax/mitochondrial apoptosis is not well understood. Using human cells, Jurkat cell line, induced with HIV-1 gp120, we studied the effects of c-FLIPL on Bax/mitochondrial apoptosis. We found that the induction of apoptosis by HIV-1 envelope protein, gp120, involved the activation of both Bax-dependent and death receptor-mediated pathways, and HIV-1 infection deceased c-FLIPL expression. Interestingly, c-FLIPL expression downregulated protein kinase C (PKC) expression at the transcript level involving activated protein-2 (AP-2). c-FLIPL expression reduced AP-2 protein levels required to promote PKC protein expression and PKC-associated inactive form of Bax, and inhibited Bax activation, suggesting that c-FLIPL inhibits Bax activation via modulating PKC expression at the transcriptional level involving AP-2 during gp120 treatment. Collectively, these findings further corroborate the concept that gp120 plays an important role, via involvement of molecules such as c-FLIPL, in apoptotic cell death due to HIV-1 infection.


Apoptosis AP-2 HIV-1 gp120 c-FLIPL PKC Bax 



We thank Dr. Mingjie Zhang, Dr. Jinhai Wang and Dr. Hira Nakhasi for critical review of the manuscript. The findings and conclusions in this article have not been formally disseminated by the FDA and should not be construed to represent any agency determination or policy.


  1. 1.
    Wang X, Wang Y, Zhang J et al (2005) FLIP protects against hypoxia/reoxygenation-induced endothelial cell apoptosis by inhibiting Bax activation. Mol Cell Biol 25:4742–4751. doi:10.1128/MCB.25.11.4742-4751.2005 CrossRefPubMedGoogle Scholar
  2. 2.
    Jaworowski A, Crowe SM (1999) Does HIV cause depletion of CD4+ T cells in vivo by the induction of apoptosis? Immunol Cell Biol 77:90–98. doi:10.1046/j.1440-1711.1999.00798.x CrossRefPubMedGoogle Scholar
  3. 3.
    Varbanov M, Espert L, Biard-Piechaczyk M (2006) Mechanisms of CD4 T-cell depletion triggered by HIV-1 viral proteins. AIDS Rev 8:221–236PubMedGoogle Scholar
  4. 4.
    Pugliese O, Boirivant M, Viora M (1997) Apoptosis induction by human immunodeficiency virus type 1 (HIV-1) gp120 peptides. Viral Immunol 10:95–102. doi:10.1089/vim.1997.10.95 CrossRefPubMedGoogle Scholar
  5. 5.
    Rasper DM, Vaillancourt JP, Hadano S et al (1998) Cell death attenuation by ‘Usurpin’, a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Cell Death Differ 5:271–288. doi:10.1038/sj.cdd.4400370 CrossRefPubMedGoogle Scholar
  6. 6.
    Micheau O (2003) Cellular FLICE-inhibitory protein: an attractive therapeutic target? Expert Opin Ther Targets 7:559–573. doi:10.1517/14728222.7.4.559 CrossRefPubMedGoogle Scholar
  7. 7.
    Wang X, Wang Y, Kim HP et al (2007) FLIP inhibits endothelial cell apoptosis during hyperoxia by suppressing Bax. Free Radic Biol Med 42:1599–1609. doi:10.1016/j.freeradbiomed.2007.02.020 CrossRefPubMedGoogle Scholar
  8. 8.
    Clark JH, Haridasse V, Glazer RI (2002) Modulation of the human protein kinase C alpha gene promoter by activator protein-2. Biochemistry 41:11847–11856. doi:10.1021/bi025600k CrossRefPubMedGoogle Scholar
  9. 9.
    Laurent-Crawford AG, Krust B, Riviere Y et al (1993) Membrane expression of HIV envelope glycoproteins triggers apoptosis in CD4 cells. AIDS Res Hum Retroviruses 9:761–773CrossRefPubMedGoogle Scholar
  10. 10.
    Laurent-Crawford AG, Coccia E, Krust B et al (1995) Membrane-expressed HIV envelope glycoprotein heterodimer is a powerful inducer of cell death in uninfected CD4+ target cells. Res Virol 146:5–17. doi:10.1016/0923-2516(96)80585-1 CrossRefPubMedGoogle Scholar
  11. 11.
    Roggero R, Robert-Hebmann V, Harrington S et al (2001) Binding of human immunodeficiency virus type 1 gp120 to CXCR4 induces mitochondrial transmembrane depolarization and cytochrome c-mediated apoptosis independently of Fas signaling. J Virol 75:7637–7650. doi:10.1128/JVI.75.16.7637-7650.2001 CrossRefPubMedGoogle Scholar
  12. 12.
    Gehri R, Hahn S, Rothen M et al (1996) The Fas receptor in HIV infection: expression on peripheral blood lymphocytes and role in the depletion of T cells. AIDS 10:9–16. doi:10.1097/00002030-199601000-00002 CrossRefPubMedGoogle Scholar
  13. 13.
    Katsikis PD, Wunderlich ES, Smith CA et al (1995) Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J Exp Med 181:2029–2036. doi:10.1084/jem.181.6.2029 CrossRefPubMedGoogle Scholar
  14. 14.
    Dyrhol-Riise AM, Stent G, Rosok BI et al (2001) The Fas/FasL system and T cell apoptosis in HIV-1-infected lymphoid tissue during highly active antiretroviral therapy. Clin Immunol 101:169–179. doi:10.1006/clim.2001.5101 CrossRefPubMedGoogle Scholar
  15. 15.
    Perfettini JL, Roumier T, Castedo M et al (2004) NF-κB and p53 are the dominant apoptosis-inducing transcription factors elicited by the HIV-1 envelope. J Exp Med 199:629–640. doi:10.1084/jem.20031216 CrossRefPubMedGoogle Scholar
  16. 16.
    Castedo M, Ferri KF, Blanco J et al (2001) Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation. J Exp Med 194:1097–1110. doi:10.1084/jem.194.8.1097 CrossRefPubMedGoogle Scholar
  17. 17.
    Ferri KF, Jacotot E, Blanco J et al (2000) Apoptosis control in syncytia induced by the HIV-1-envelope glycoprotein complex. Role of mitochondria and caspases. J Exp Med 192:1081–1092. doi:10.1084/jem.192.8.1081 CrossRefPubMedGoogle Scholar
  18. 18.
    Day TW, Huang S, Safa AR (2008) c-FLIP knockdown induces ligand-independent DR5-, FADD-, caspase-8-, and caspase-9-dependent apoptosis in breast cancer cells. Biochem Pharmacol 76:1694–1704. doi:10.1016/j.bcp.2008.09.007 CrossRefPubMedGoogle Scholar
  19. 19.
    Neri LM, Borgatti P, Capitani S et al (2002) Protein kinase C isoforms and lipid second messengers: a critical nuclear partnership? Histol Histopathol 17:1311–1316PubMedGoogle Scholar
  20. 20.
    Trauzold A, Schmiedel S, Sipos B et al (2003) PKCmu prevents CD95-mediated apoptosis and enhances proliferation in pancreatic tumour cells. Oncogene 22:8939–8947. doi:10.1038/sj.onc.1207001 CrossRefPubMedGoogle Scholar
  21. 21.
    Gomez-Angelats M, Cidlowski JA (2001) Protein kinase C regulates FADD recruitment and death-inducing signaling complex formation in Fas/CD95-induced apoptosis. J Biol Chem 276:44944–44952. doi:10.1074/jbc.M104919200 CrossRefPubMedGoogle Scholar
  22. 22.
    McJilton MA, Van Sikes C, Wescott GG et al (2003) Protein kinase Cepsilon interacts with Bax and promotes survival of human prostate cancer cells. Oncogene 22:7958–7968. doi:10.1038/sj.onc.1206795 CrossRefPubMedGoogle Scholar
  23. 23.
    Accornero P, Radrizzani M, Carè A et al (1998) HIV/gp120 and PMA/ionomycin induced apoptosis but not activation induced cell death require PKC for Fas-L upregulation. FEBS Lett 436:461–465. doi:10.1016/S0014-5793(98)01127-2 CrossRefPubMedGoogle Scholar
  24. 24.
    Huang MB, Bond VC (2000) Involvement of protein kinase C in HIV-1 gp120-induced apoptosis in primary endothelium. J Acquir Immune Defic Syndr 25:375–389. doi:10.1097/00126334-200012150-00001 CrossRefPubMedGoogle Scholar
  25. 25.
    Yu G, Shen FS, Sturch S et al (1995) Regulation of HIV-1 gag protein subcellular targeting by protein kinase C. J Biol Chem 270:4792–4796. doi:10.1074/jbc.270.9.4792 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  1. 1.Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases Center for Biologics Evaluation and Research, Food and Drug AdministrationBethesdaUSA
  2. 2.Department of Pharmacology and Oncology and Lombardi Cancer CenterGeorgetown University School of MedicineWashingtonUSA

Personalised recommendations