DOI QR코드

DOI QR Code

Hepatitis B virus X protein enhances NFκB activity through cooperating with VBP1

  • Kim, Sang-Yong (Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University) ;
  • Kim, Jin-Chul (Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University) ;
  • Kim, Jeong-Ki (Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University) ;
  • Kim, Hye-Jin (Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University) ;
  • Lee, Hee-Min (Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University) ;
  • Choi, Mi-Sun (Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University) ;
  • Maeng, Pil-Jae (Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University) ;
  • Ahn, Jeong-Keun (Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University)
  • Received : 2007.11.09
  • Accepted : 2007.11.21
  • Published : 2008.02.29

Abstract

Hepatitis B virus X protein (HBx) is essential for hepatitis B virus infection and exerts a pleiotropic effect on various cellular machineries. HBx has been also demonstrated as an indirect transcriptional transactivator of various different viral and cellular promoters. In addition, HBx is involved in the development of various liver diseases including hepatocellular carcinoma. However the mechanism of HBx in hepatocellular carcinogenesis remains largely unknown. In this study, to identify possible new cellular proteins interacting with HBx, we carried out yeast two-hybrid assay. We obtained several possible cellular partners including VBP1, a binding factor for VHL tumor suppressor protein. The direct physical interaction between HBx and VBP1 in vitro and in vivo was confirmed by immunoprecipitation assay. In addition, we found that VBP1 facilitates HBx-induced $NF{\kappa}B$ activation and cell proliferation. These results implicate the important role of HBx in the development of hepatocellular carcinoma through its interaction with VBP1.

Keywords

References

  1. Henkler, F. F. and Koshy, R. (1996) Hepatitis B virus transcriptional activators: mechanisms and possible role in oncogenesis. J. Viral Hepat. 3, 109-121 https://doi.org/10.1111/j.1365-2893.1996.tb00001.x
  2. Nakamoto, Y., Guidotti, L. G., Kuhlen, C. V., Fowler, P. and Chisari, F. V. (1998) Immune pathogenesis of hepatocellular carcinoma. J. Exp. Med. 188, 341-350 https://doi.org/10.1084/jem.188.2.341
  3. Feitelson, M. A. and Lee, J. (2007) Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Lett. 252, 157-170 https://doi.org/10.1016/j.canlet.2006.11.010
  4. Ozkal, P., Ilgin-Ruhi, H., Akdogan, M., Elhan, A. H., Kacar, S. and Sasmaz, N. (2005) The genotoxic effects of hepatitis B virus to host DNA. Mutagenesis 20, 147-150 https://doi.org/10.1093/mutage/gei021
  5. Cromlish, J. A. (1996) Hepatitis B virus-induced hepatocellular carcinoma: possible roles for HBx. Trends Microbiol. 4, 270-274 https://doi.org/10.1016/0966-842X(96)10046-9
  6. Rossner, M. T. (1992) Review: hepatitis B virus X-gene product: a promiscuous transcriptional activator. J. Med. Virol. 36, 101-117 https://doi.org/10.1002/jmv.1890360207
  7. Bouchard, M. J., Wang L. H. and Schneider, R. J. (2001) Calcium signaling by HBx protein in hepatitis B virus DNA replication. Science 294, 2376-2378 https://doi.org/10.1126/science.294.5550.2376
  8. Klein, N. P., Bouchard, M. J., Wang, L. H., Kobarg, C. and Schneider, R. J. (1999) Src kinases involved in hepatitis B virus replication. Embo J. 18, 5019-5027 https://doi.org/10.1093/emboj/18.18.5019
  9. Kim, S. Y., Kim, J. K., Kim, H. J. and Ahn, J. K. (2005) Hepatitis B virus X protein sensitizes UV-induced apoptosis by transcriptional transactivation of Fas ligand gene expression. IUBMB Life 57, 651-658 https://doi.org/10.1080/15216540500239697
  10. Benn, J. and Schneider, R. J. (1994) Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc. Natl. Acad. Sci. U. S. A. 91, 10350-10354 https://doi.org/10.1073/pnas.91.22.10350
  11. Cross, J. C., Wen, P. and Rutter, W. J. (1993) Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/threonine kinases. Proc. Natl. Acad. Sci. U. S. A. 90, 8078-8082 https://doi.org/10.1073/pnas.90.17.8078
  12. Kekule, A. S., Lauer, U., Weiss, L., Luber, B. and Hofschneider, P. H. (1993) Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature 361, 742-745 https://doi.org/10.1038/361742a0
  13. Natoli, G., Avantaggiati, M. L., Chirillo, P., Puri, P. L., Ianni, A., Balsano, C. and Levrero, M. (1994) Ras- and Raf-dependent activation of c-jun transcriptional activity by the hepatitis B virus transactivator pX. Oncogene 9, 2837-2843
  14. Arii, M., Takada, S. and Koike, K. (1992) Identification of three essential regions of hepatitis B virus X protein for trans-activation function. Oncogene 7, 397-403
  15. Zhang, X., Zhang, H. and Ye, L. (2006) Effects of hepatitis B virus X protein on the development of liver cancer. J Lab. Clin. Med. 147, 58-66 https://doi.org/10.1016/j.lab.2005.10.003
  16. Madden, C. R., Finegold, M. J. and Slagle, B. L. (2001) Hepatitis B virus X protein acts as a tumor promoter in development of diethylnitrosamine-induced preneoplastic lesions. J. Virol. 75, 3851-3858 https://doi.org/10.1128/JVI.75.8.3851-3858.2001
  17. Yu, D. Y., Moon, H. B., Son, J. K., Jeong, S., Yu, S. L., Yoon, H., Han, Y. M., Lee, C. S., Park, J. S., Lee, C. H., Hyun, B. H., Murakami, S. and Lee, K. K. (1999) Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein. J. Hepatol. 31, 123-132 https://doi.org/10.1016/S0168-8278(99)80172-X
  18. Zhu, H., Wang, Y., Chen, J., Cheng, G. and Xue, J. (2004) Transgenic mice expressing hepatitis B virus X protein are more susceptible to carcinogen induced hepatocarcinogenesis. Exp. Mol. Pathol. 76, 44-50 https://doi.org/10.1016/j.yexmp.2003.09.001
  19. Chan, D. W. and Ng, I. O. (2006) Knock-down of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells. J. Pathol. 208, 372-380 https://doi.org/10.1002/path.1901
  20. Cheng, A. S., Wong, N., Tse, A. M., Chan, K. Y., Chan, K. K., Sung, J. J. and Chan, H. L. (2007) RNA interference targeting HBx suppresses tumor growth and enhances cisplatin chemosensitivity in human hepatocellular carcinoma. Cancer Lett. 253, 43-52 https://doi.org/10.1016/j.canlet.2007.01.004
  21. Okamoto, T., Sanda, T. and Asamitsu, K. (2007) NF-kappa B signaling and carcinogenesis. Curr. Pharm. Des. 13, 447-462 https://doi.org/10.2174/138161207780162944
  22. Rosette, C. and Karin, M. (1996) Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science 274, 1194-1197 https://doi.org/10.1126/science.274.5290.1194
  23. Rayet, B. and Gelinas, C. (1999) Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18, 6938-6947 https://doi.org/10.1038/sj.onc.1203221
  24. Um, H. R., Lim, W. C., Chae, S. Y., Park, S., Park, J. H. and Cho, H. (2007) Raf-1 and protein kinase B regulate cell survival through the activation of NF-kappaB in hepatitis B virus X-expressing cells. Virus Res. 125, 1-8 https://doi.org/10.1016/j.virusres.2006.11.007
  25. Factor, V., Oliver, A. L., Panta, G. R., Thorgeirsson, S. S., Sonenshein, G. E. and Arsura, M. (2001) Roles of Akt/PKB and IKK complex in constitutive induction of NF-kappaB in hepatocellular carcinomas of transforming growth factor alpha/c-myc transgenic mice. Hepatology 34, 32-41 https://doi.org/10.1053/jhep.2001.25270
  26. Yun, C., Um, H. R., Jin, Y. H., Wang, J. H., Lee, M. O., Park, S., Lee, J. H. and Cho, H. (2002) NF-kappaB activation by hepatitis B virus X (HBx) protein shifts the cellular fate toward survival. Cancer Lett. 184, 97-104 https://doi.org/10.1016/S0304-3835(02)00187-8
  27. Su, F. and Schneider, R. J. (1996) Hepatitis B virus HBx protein activates transcription factor NF-kappaB by acting on multiple cytoplasmic inhibitors of rel-related proteins. J. Virol. 70, 4558-4566
  28. An, J. and Rettig, M. B. (2005) Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor kappa B activity. Mol. Cell. Biol. 25, 7546-7556 https://doi.org/10.1128/MCB.25.17.7546-7556.2005
  29. Brinke, A., Green, P. M. and Giannelli, F. (1997) Characterization of the gene (VBP1) and transcript for the von Hippel-Lindau binding protein and isolation of the highly conserved murine homologue. Genomics 45, 105-112 https://doi.org/10.1006/geno.1997.4902
  30. Tsuchiya, H., Iseda, T. and Hino, O. (1996) Identification of a novel protein (VBP-1) binding to the von Hippel-Lindau (VHL) tumor suppressor gene product. Cancer Res. 56, 2881-2885
  31. Oh, J. C., Jeong, D. L., Kim, I. K. and Oh, S. H. (2003) Activation of calcium signaling by hepatitis B virus-X protein in liver cells. Exp. Mol. Med. 35, 301-309 https://doi.org/10.1038/emm.2003.41
  32. Zhang, J. L., Zhao, W. G., Wu, K. L., Wang, K., Zhang, X., Gu, C. F., Li, Y., Zhu, Y. and Wu, J. G. (2005) Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis through interacting with a serine protease Hepsin. Arch. Virol. 150, 721-741 https://doi.org/10.1007/s00705-004-0446-0
  33. Meyer, M., Caselmann, W. H., Schluter, V., Schreck, R., Hofschneider, P. H. and Baeuerle, P. A. (1992) Hepatitis B virus transactivator MHBst: activation of NF-kappa B, selective inhibition by antioxidants and integral membrane localization. Embo J. 11, 2991-3001

Cited by

  1. Interferon-α sensitizes HBx-expressing hepatocarcinoma cells to chemotherapeutic drugs through inhibition of HBx-mediated NF-κB activation vol.10, pp.1, 2013, https://doi.org/10.1186/1743-422X-10-168
  2. NF-κB signaling mediates the induction of MTA1 by hepatitis B virus transactivator protein HBx vol.29, pp.8, 2010, https://doi.org/10.1038/onc.2009.404
  3. Therapeutic microRNAs targeting the NF-kappa B signaling circuits of cancers vol.81, 2015, https://doi.org/10.1016/j.addr.2014.09.004
  4. Prefoldins Negatively Regulate Cold Acclimation in Arabidopsis thaliana by Promoting Nuclear Proteasome-Mediated HY5 Degradation vol.10, pp.6, 2017, https://doi.org/10.1016/j.molp.2017.03.012
  5. NF-κB as a potential therapeutic target in microbial diseases vol.8, pp.4, 2012, https://doi.org/10.1039/c2mb05335g
  6. HBx-Induced NF-κB Signaling in Liver Cells Is Potentially Mediated by the Ternary Complex of HBx with p22-FLIP and NEMO vol.8, pp.3, 2013, https://doi.org/10.1371/journal.pone.0057331
  7. Prefoldin Subunits Are Protected from Ubiquitin-Proteasome System-mediated Degradation by Forming Complex with Other Constituent Subunits vol.286, pp.22, 2011, https://doi.org/10.1074/jbc.M110.216259
  8. HBx-induced MiR-1269b in NF-κB dependent manner upregulates cell division cycle 40 homolog (CDC40) to promote proliferation and migration in hepatoma cells vol.14, pp.1, 2016, https://doi.org/10.1186/s12967-016-0949-y
  9. Prefoldin 1 promotes EMT and lung cancer progression by suppressing cyclin A expression vol.36, pp.7, 2017, https://doi.org/10.1038/onc.2016.257
  10. Involvement of the NF-κB pathway in multidrug resistance induced by HBx in a hepatoma cell line vol.18, pp.10, 2011, https://doi.org/10.1111/j.1365-2893.2011.01463.x
  11. High-level expression and large-scale preparation of soluble HBx antigen fromEscherichia coli vol.54, pp.3, 2009, https://doi.org/10.1042/BA20090116
  12. Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/β-catenin signaling vol.300, pp.2, 2011, https://doi.org/10.1016/j.canlet.2010.09.018
  13. Nuclear functions of prefoldin vol.4, pp.7, 2014, https://doi.org/10.1098/rsob.140085
  14. Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression vol.50, pp.2, 2009, https://doi.org/10.1002/hep.23008
  15. Structural characterization of an intrinsically unfolded mini-HBX protein from hepatitis B virus vol.34, pp.2, 2012, https://doi.org/10.1007/s10059-012-0060-z
  16. The function of miRNAs in hepatocarcinogenesis induced by hepatitis B virus X protein vol.38, pp.2, 2017, https://doi.org/10.3892/or.2017.5716
  17. VBP1 represses cancer metastasis by enhancing HIF-1α degradation induced by pVHL vol.285, pp.1, 2018, https://doi.org/10.1111/febs.14322
  18. Complexity on modulation of NF-κB pathways by hepatitis B and C: A double-edged sword in hepatocarcinogenesis pp.00219541, 2019, https://doi.org/10.1002/jcp.28249