The human T-cell leukemia virus type-1 tax oncoprotein dissociates NF-κB p65RelA-Stathmin complexes and causes catastrophic mitotic spindle damage and genomic instability

Genomic instability is a hallmark of many cancers; however, the molecular etiology of chromosomal dysregulation is not well understood. The human T-cell leukemia virus type-1 (HTLV-1) oncoprotein Tax activates NF-kappa B-signaling and induces DNA-damage and aberrant chromosomal segregation through diverse mechanisms which contribute to viral carcinogenesis. Intriguingly, Stathmin/oncoprotein-18 (Op-18) depolymerizes tubulin and interacts with the p65(RelA) subunit and functions as a cofactor for NF-kappa B-dependent transactivation. We thus hypothesized that the dissociation of p65(RelA)-Stathmin/Op-18 complexes by Tax could lead to the catastrophic destabilization of microtubule (MT) spindle fibers during mitosis and provide a novel mechanistic link between NF-kappa B-signaling and genomic instability. Here we report that the inhibition of Stathmin expression by the retroviral latency protein, p30(II), or knockdown with siRNA-stathmin, dampens Tax-mediated NF-kappa B transactivation and counters Tax-induced genomic instability and cytotoxicity. The Tax-G148V mutant, defective for NF-kappa B activation, exhibited reduced p65(RelA)-Stathmin binding and diminished genomic instability and cytotoxicity. Dominant-negative inhibitors of NF-kappa B also prevented Tax-induced multinucleation and apoptosis. Moreover, cell clones containing the infectious HTLV-1 ACH. p30(II) mutant provirus, impaired for p30(II) production, exhibited increased multinucleation and the accumulation of cytoplasmic tubulin aggregates following nocodozole-treatment. These findings allude to a mechanism whereby NF-kappa B-signaling regulates tubulin dynamics and mitotic instability through the modulation of p65(RelA)-Stathmin/Op-18 interactions, and support the notion that p3(II) enhances the survival of Tax-expressing HTLV-1-transformed cells.