passages: PMID-22740410__text
passages: abstract
passages: HTLV-1 tax-induced rapid senescence is driven by the transcriptional activity of NF-kappaB and depends on chronically activated IKKalpha and p65/RelA. 
  The HTLV-1 oncoprotein Tax is a potent activator of classical and alternative NF-kappaB pathways and is thought to promote cell proliferation and transformation via NF-kappaB activation. We showed recently that hyperactivation of NF-kappaB by Tax triggers a cellular senescence response (H. Zhi et al., PLoS Pathog. 7:e1002025, 2011). Inhibition of NF-kappaB activation by expression of I-kappaBalpha superrepressor or by small hairpin RNA (shRNA)-mediated knockdown of p65/RelA rescues cells from Tax-induced rapid senescence (Tax-IRS). Here we demonstrate that Tax-IRS is driven by the transcriptional activity of NF-kappaB. Knockdown of IKKgamma, the primary Tax target, by shRNAs abrogated Tax-mediated activation of both classical and alternative NF-kappaB pathways and rendered knockdown cells resistant to Tax-IRS. Consistent with a critical role of IKKalpha in the transcriptional activity of NF-kappaB, IKKalpha deficiency drastically decreased NF-kappaB trans-activation by Tax, although it only modestly reduced Tax-mediated I-kappaBalpha degradation and NF-kappaB nuclear localization. In contrast, although IKKbeta knockdown attenuated Tax-induced NF-kappaB transcriptional activation, the residual NF-kappaB activation in IKKbeta-deficient cells was sufficient to trigger Tax-IRS. Importantly, the phenotypes of NIK and TAK1 knockdown were similar to those of IKKalpha and IKKbeta knockdown, respectively. Finally, double knockdown of RelB and p100 had a minor effect on senescence induction by Tax. These data suggest that Tax, through its interaction with IKKgamma, helps recruit NIK and TAK1 for IKKalpha and IKKbeta activation, respectively. In the presence of Tax, the delineation between the classical and alternative NF-kappaB pathways becomes obscured. The senescence checkpoint triggered by Tax is driven by the transcriptional activity of NF-kappaB, which depends on activated IKKalpha and p65/RelA.
  