Tax, the viral oncoprotein of human T cell leukemia virus type 1, which has been etiologically linked to the development of adult T cell leukemia, is a predominantly nuclear protein that colocalizes with cellular proteins in nuclear foci, known as Tax speckled structures (TSS). Tax has recently been shown to shuttle between the nucleus and cytoplasm of infected cells, resulting in altered Tax functions. Conditions or mechanisms that regulate the distribution of Tax between the cytoplasm and nucleus remain to be identified. Since Tax has been shown to promote genome instability by perturbing cell cycle progression and the repair of DNA following DNA damage, we examined the effects of genotoxic and other cellular stressors on the subcellular distribution and protein partners of Tax. Following stress, we observed increased cytoplasmic localization of Tax combined with a decreased number of TSS. In addition stress resulted in altered interactions of Tax with host cell proteins, since we observed decreased colocalization with sc35, and identified a new interaction with the nuclear export protein CRM1. The interaction of Tax with CRM1 following stress is consistent with nuclear export through the CRM1 nuclear export pathway. This was confirmed using both leptomycin B, a specific inhibitor of this pathway and a nuclear export defective Tax mutant. These results suggest that the subcellular distribution of Tax and interactions between Tax and cellular proteins respond dynamically to cellular signals. In fact, increased mono-ubiquitination (UB) of Tax was observed in response to DNA damage and appears to play an important role in regulating nuclear export, since Tax mutants that are not able to be ubiquitinated are not exported to the cytoplasm in response to stress. Consistent with this, we have demonstrated that a Tax- UB fusion protein is predominantly expressed in the cytoplasm of transfected cells. We are currently investigating the possibility that changes in Tax localization and binding partners may dysregulate cellular processes that contribute to cellular transformation.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]