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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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Conference name:
15th International Conference on Human Retroviruses: HTLV and Related Viruses