Knockdown of Bcl-3 Inhibits Cell Growth and Induces DNA Damage in HTLV-1-infected Cells)

  • Gao, Cai (Research Center for Immunology, Xinxiang Medical University) ;
  • Wang, Xia (Research Center for Immunology, Xinxiang Medical University) ;
  • Chen, Lin (Research Center for Immunology, Xinxiang Medical University) ;
  • Wang, Jin-Heng (Research Center for Immunology, Xinxiang Medical University) ;
  • Gao, Zhi-Tao (Research Center for Immunology, Xinxiang Medical University) ;
  • Wang, Hui (Research Center for Immunology, Xinxiang Medical University)
  • Published : 2013.01.31


Oncoprotein Bcl-3 is perceived as an unusual member of $I{\kappa}B$ family since it can both stimulate and suppress NF-${\kappa}B$ activation. Aberrant Bcl-3 results in increased cell proliferation and survival, suggesting a contribution to malignant potential and elevated levels of Bcl-3 have been observed in many HTLV-1-infected T cell lines and ATL cells. To investigate the specific roles of Bcl-3 in HTLV-1-infected cells, we knocked down Bcl-3 expression using shRNA and then examined the consequences with regard to DNA damage and cell proliferation, as well as NF-${\kappa}B$ activation. The HTLV-1 encoded protein Tax promotes Bcl-3 expression and nuclear translocation. In HTLV-1-infected cells, Bcl-3 knockdown obviously induced DNA damage. Cell growth and NF-${\kappa}B$ activation were reduced in HTLV-1-infected or Tax positive cells when Bcl-3 expression was decreased. Together, our results revealed positive roles of Bcl-3 in DNA stabilization, growth and NF-${\kappa}B$ activation in HTLV-1-infected cells.


Supported by : National Natural Science Foundation of China


  1. Na SY, Choi HS, Kim JW, et al (1998). Bcl3, an IkappaB protein, as a novel transcription coactivator of the retinoid X receptor. J Biol Chem, 273, 30933-8.
  2. O’Mahony AM (2004). Human T-cell Lymphotropic Virus Type 1 Tax Induction of Biologically Active NF- B Requires I B Kinase-1-mediated Phosphorylation of RelA/p65. J Biol Chem, 279, 18137-45.
  3. Ohno H, Takimoto G, McKeithan TW (1990). The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control. Cell, 60, 991-7.
  4. Park SG, Chung C, Kang H, et al (2006). Up-regulation of cyclin D1 by HBx is mediated by NF-kappaB2/BCL3 complex through kappaB site of cyclin D1 promoter. J Biol Chem, 281, 31770-777.
  5. Rangelova S, Kirschnek S, Strasser A, et al (2008). FADD and the NF-kappaB family member Bcl-3 regulate complementary pathways to control T-cell survival and proliferation. Immunology, 125, 549-57.
  6. Saito K, Saito M, Taniura N, et al (2010). Activation of the PI3K-Akt pathway by human T cell leukemia virus type 1 (HTLV-1) oncoprotein Tax increases Bcl3 expression, which is associated with enhanced growth of HTLV-1-infected T cells. Virology, 403, 173-80.
  7. Shvarzbeyn J, Huleihel M (2011). Effect of propolis and caffeic acid phenethyl ester (CAPE) on NF${\kappa}B$ activation by HTLV-1 Tax. Antiviral Res, 90, 108-15.
  8. Sun SC, Elwood J, Beraud C, et al (1994). Human T-cell leukemia virus type I Tax activation of NF-kappa B/Rel involves phosphorylation and degradation of I kappa B alpha and RelA (p65)-mediated induction of the c-rel gene. Mol Cell Biol, 14, 7377-84.
  9. Valenzuela JO, Hammerbeck CD, Mescher MF (2005). Cutting edge: Bcl-3 up-regulation by signal 3 cytokine (IL-12) prolongs survival of antigen-activated CD8 T cells. J Immunol, 174, 600-4.
  10. Viatour P, Dejardin E, Warnier M, et al (2004). GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. Mol Cell, 16, 35-45.
  11. Watanabe N, Wachi S, Fujita T (2003). Identification and characterization of BCL-3-binding protein: implications for transcription and DNA repair or recombination. J Biol Chem, 278, 26102-10.
  12. Wessells J, Baer M, Young HA, et al (2004). BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages. J Biol Chem, 279, 49995-50003.
  13. Yasunaga J, Lin FC, Lu X, et al (2011). Ubiquitin-Specific Peptidase 20 Targets TRAF6 and Human T Cell Leukemia Virus Type 1 Tax To Negatively Regulate NF- B Signaling. J Virol, 85, 6212-9.
  14. Zamora R, Espinosa M, Ceballos-Cancino G, et al (2010). Depletion of the oncoprotein Bcl-3 induces centrosome amplification and aneuploidy in cancer cells. Mol Cancer, 9, 223.
  15. Bauer A, Villunger A, Labi V, et al (2006). The NF-kappaB regulator Bcl-3 and the BH3-only proteins Bim and Puma control the death of activated T cells. Proc Natl Acad Sci U S A , 103, 10979-84.
  16. Boulton SJ, Gartner A, Reboul J, et al (2002). Combined functional genomic maps of the C. elegans DNA damage response. Science, 295, 127-31.
  17. Bours V, Franzoso G, Azarenko V, et al (1993). The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers. Cell, 72, 729-39.
  18. Courtois G, Gilmore TD (2006). Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene, 25, 6831-43.
  19. Everett RD (2011). The use of fluorescence microscopy to study the association between herpesviruses and intrinsic resistance factors. Viruses, 3, 2412-24.
  20. Harhaj E, Harhaj N (2005). Mechanisms of Persistent NF-${\kappa}B$ Activation by HTLV-I Tax. IUBMB Life, 57, 83-91.
  21. Hishiki T, Ohshima T, Ego T, et al (2007). BCL3 acts as a negative regulator of transcription from the human T-cell leukemia virus type 1 long terminal repeat through interactions with TORC3. J Biol Chem, 282, 28335-43.
  22. Kashatus D, Cogswell P, Baldwin AS (2006). Expression of the Bcl-3 proto-oncogene suppresses p53 activation. Genes Dev, 20, 225-35.
  23. Kim Y.M., Sharma N, Nyborg JK (2008). The proto-oncogene Bcl3, induced by Tax, represses Tax-mediated transcription via p300 displacement from the human T-cell leukemia virus type 1 promoter. J Virol, 82, 11939-47.
  24. McKeithan TW, Rowley JD, Shows TB, et al (1987). Cloning of the chromosome translocation breakpoint junction of the t(14;19) in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A, 84, 9257-60.

Cited by

  1. Regulation of the Adaptive Immune Response by the IκB Family Protein Bcl-3 vol.5, pp.2, 2016,