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      NF-κB hyper-activation by HTLV-1 Tax induces cellular senescence, but can be alleviated by the viral anti-sense protein HBZ

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      1 , 1 , 1 , 1 , 2 , 1 ,
      Retrovirology
      BioMed Central
      15th International Conference on Human Retroviruses: HTLV and Related Viruses
      5-8 June 2011

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          Abstract

          Activation of I-κB kinases (IKKs) and NF-κB by the human T lymphotrpic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, is thought to promote cell proliferation and transformation. Paradoxically, expression of Tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors, p21CIP1/WAF1 and p27KIP1, which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21CIP1/WAF1-/p27KIP1-mediated senescence constitutes a checkpoint against IKK/NF-κB hyper-activation. Senescence induction by Tax is attenuated by mutations in Tax that reduce IKK/NF-κB activation and prevented by blocking NF-κB using a degradation-resistant mutant of I-κBα despite constitutive IKK activation. Small hairpin RNA-mediated knockdown indicates that RelA induces this senescence program by acting upstream of the anaphase promoting complex and RelB to stabilize p27KIP1 protein and p21CIP1/WAF1 mRNA respectively. Finally, we show that downregulation of NF-κB by the HTLV-1 anti-sense protein, HBZ, delay or prevent the onset of Tax-induced senescence. We propose that the balance between Tax and HBZ expression determines the outcome of HTLV-1 infection. Robust HTLV-1 replication and elevated Tax expression drive IKK/NF-κB hyperactivation and trigger senescence. HBZ, however, modulates Tax-mediated viral replication and NF-κB activation, thus allowing HTLV-1-infected cells to proliferate, persist, and evolve. Finally, inactivation of the senescence checkpoint can facilitate persistent NF-κB activation and leukemogenesis.

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          Author and article information

          Conference
          Retrovirology
          Retrovirology
          BioMed Central
          1742-4690
          2011
          6 June 2011
          : 8
          : Suppl 1
          : A200
          Affiliations
          [1 ]Department of Microbiology and Immunology Uniformed Services, University of the Health Sciences, Bethesda, MD, 20814, USA
          [2 ]Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
          Article
          1742-4690-8-S1-A200
          10.1186/1742-4690-8-S1-A200
          3112677
          36053117-e44d-40f1-b493-0c30cb473dca
          Copyright ©2011 Zhi et al; licensee BioMed Central Ltd.

          This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

          15th International Conference on Human Retroviruses: HTLV and Related Viruses
          Leuven and Gembloux, Belgium
          5-8 June 2011
          History
          Categories
          Meeting Abstract

          Microbiology & Virology
          Microbiology & Virology

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