Fig. 2

CIITA inhibits the Tax-1-mediated activation of the canonical NF-kB pathway. The oncogenic potential of Tax-1 is mostly due to its ability to constitutively activate NF-kB pathways. Tax-1 deregulates both the canonical and the noncanonical NF-kB pathway, by acting at different levels. In the canonical pathway, Tax-1 interacts with the gamma (γ) subunit of the trimeric IkB kinase (IKK), and activates IKK complex. The activated IKK phosphorylates IkB inhibitor bound to p50/RelA NFκB heterodimer. Following phosphorylation, IkB is degraded and the p50/RelA NF-kB complex migrates into the nucleus activating NF-kB target genes. In the non-canonical pathway, Tax-1 interacts and activates IKKα, which phosphorylates the inhibitory p100 subunit, thus inducing the activation and migration of the p52-/RelB NF-kB heterodimer into the nucleus. Moreover, Tax-1 promotes NF-kB activation in the nucleus by interacting with RelA and stabilizing the binding of p50/RelA to NF-kB-responsive promoters. CIITA exploits different strategies to suppress Tax-1-mediated NF-kB activation by acting in the nucleus and in the cytoplasm. In the cytoplasm [1], CIITA interacts with Tax-1 and this association does not prevent Tax-1 binding to IKKγ subunit of the IKK complex. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing retention of the inactive p50/RelA/IkB complex in the cytoplasm. In the nucleus [2], nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NF-kB-responsive genes [2]