title: NF-κB hyper-activation by HTLV-1 tax induces cellular senescence, but can be alleviated by the viral anti-sense protein HBZ.
abstract: Activation of I-κB kinases (IKKs) and NF-κB by the human T lymphotropic 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, p21(CIP1/WAF1) and p27(KIP1), which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21(CIP1/WAF1)-/p27(KIP1)-mediated senescence constitutes a checkpoint against IKK/NF-κB hyper-activation. Senescence induced by Tax in HeLa cells 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 p27(KIP1) protein and p21(CIP1/WAF1) mRNA respectively. Finally, we show that down-regulation 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 hyper-activation 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.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhi
authors.forename: Liangpeng
authors.initials: L
authors.lastname: Yang
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Kuo
authors.forename: Yik-Khuan
authors.initials: YK
authors.lastname: Ho
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.forename: Chou-Zen
authors.initials: CZ
authors.lastname: Giam
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology*; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D015536:Down-Regulation; D016356:Gene Products, tax / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012191:Retroviridae Proteins; D014764:Viral Proteins / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016356:Gene Products, tax; C479751:HBZ protein, human T-cell leukemia virus type I; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D012191:Retroviridae Proteins; D014764:Viral Proteins; D000072000:NF-KappaB Inhibitor alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27