RKIP Downregulation Induces the HBx-Mediated Raf-1 Mitochondrial Translocation

  • 투고 : 2010.12.20
  • 심사 : 2011.02.22
  • 발행 : 2011.05.28


The Raf-1 kinase inhibitory protein (RKIP) can regulate multiple key signaling pathways. Specifically, RKIP binds to Raf-1 kinase and inhibits the Ras-Raf-1-MEK1/2- ERK1/2 pathway. Additionally, Raf-1 has been shown to translocate to mitochondria and thereby protect cells from stress-mediated apoptosis. Recently, HBx was found to stimulate the mitochondrial translocation of Raf-1, contributing to the anti-apoptotic effect. We found that RKIP was downregulated during HBx-mediated hepatocarcinogenesis. In this study, we show that RKIP bound to Raf-1 and consequently inhibited the translocation of Raf-1 into mitochondria. This promoted the apoptosis of cells treated with apoptotic stimulus. Thus, the downregulation of RKIP increased the level of free Raf-1 and thereby elevated the mitochondrial translocation of Raf-1 during HBx-mediated hepatocarcinogenesis. The elevated Raf-1 mitochondrial translocation induced the increased anti-apoptotic effect and subsequently promoted HBx-mediated hepatocarcinogenesis.



  1. Alexia, C., G. Fallot, M. Lasfer, G. Schweizer-Groyer, and A. Groyer. 2004. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signaling in hepatocarcinogenesis and in the resistance of the hepatocarcinoma cells against drug-induced apoptosis. Biochem. Pharmacol. 68: 1003-1015.
  2. Chen, J. and A. Siddiqui. 2007. Hepatitis B virus X protein stimulates the mitochondrial translocation of Raf-1 via oxidative stress. J. Virol. 81: 6757-6760.
  3. Corbit, K. C., N. Trakul, E. M. Eves, B. Diaz, M. Marshall, and M. R. Rosner. 2003. Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. J. Biol. Chem. 278: 13061-13068.
  4. Granovsky, A. E. and M. R. Rosner. 2008. Raf kinase inhibitory protein: A signal transduction modulator and metastasis suppressor. Cell Res. 18: 452-457.
  5. Klysik, J., S. J. Theroux, J. M. Sedivy, J. S. Moffit, and K. Boekelheide. 2008. Signaling crossroads: The function of Raf kinase inhibitory protein in cancer, the central nervous system and reproduction. Cell Signal. 20: 1-9.
  6. Lee, H. C., B. Tian, J. M. Sedivy, J. R. Wands, and M. Kim. 2006. Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology. 131: 1208-1217.
  7. Lee, T. K., T. C. Lau, and I. O. Ng. 2002. Doxorubicin-induced apoptosis and chemosensitivity in hepatoma cell lines. Cancer Chemother. Pharmacol. 49: 78-86.
  8. Lee, Y. I., J. M. Hwang, J. H. Im, Y. I. Lee, N. S. Kim, D. G. Kim, et al. 2004. Human hepatitis B virus-X protein alters mitochondrial function and physiology in human liver cells. J. Biol. Chem. 279: 15460-15471.
  9. Kim, S.-Y., P. Y. Lee, H.-J. Shin, D. H. Kim, S. Kang, H.-B. Moon, et al. 2009. Proteomic analysis of liver tissue from HBxtransgenic mice at early stages of hepatocarcinogenesis. Proteomics 9: 5056-5066.
  10. Neuveut, C., Y. Wei, and M. A. Buendia. 2010. Mechanisms of HBV-related hepatocarcinogenesis. J. Hepatol. 52: 594-604.
  11. Odabaei, G., D. Chatterjee, A. R. Jazirehi, L. Goodglick, K. Yeung, and B. Bonavida. 2004. Raf-1 kinase inhibitor protein: Structure, function, regulation of cell signaling, and pivotal role in apoptosis. Adv. Cancer Res. 91: 169-200.
  12. Schuierer, M. M., F. Bataille, T. S. Weiss, C. Hellerbrand, and A. K. Bosserhoff. 2006. Raf kinase inhibitor protein is downregulated in hepatocellular carcinoma. Oncol. Rep. 16: 451-456.
  13. Tang, H., N. Oishi, S. Kaneko, and S. Murakami. 2006. Molecular functions and biological roles of hepatitis B virus X protein. Cancer Sci. 97: 977-983.
  14. Xu, Y.-F., Y. Yi, S.-J. Qiu, Q. Gao, Y.-W. Li, C.-X. Dai, et al. 2010. PEBP1 downregulation is associated to poor prognosis in HCC related to hepatitis B infection. J. Hepatol. 53: 872-879.
  15. Jeon, Y.-J., D.-H. Kim, H. Jung, S. J. Chung, S.-W. Chi, S. Cho, et al. 2010. Annexin A4 interacts with the NF-$\kappa$B p50 subunit and modulates NF-$\kappa$B transcriptional activity in a $Ca^{2+}$-dependent manner. Cell Mol. Life Sci. 67: 2271-2281.

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