Nucleocytoplasmic shuttling and the biological activity of mouse survivin are regulated by an active nuclear export signal

Abstract

Survivin appears to function as a regulator of cell division and as an apoptosis inhibitor in many species. Here, we characterized the nucleocytoplasmic transport of mouse survivin140, and its splice variants survivin121 and survivin40. We show that the dynamic intracellular localization of survivin140 is mediated by a Crm1-dependent nuclear export signal (NES) present also in survivin121, but absent in survivin40. In contrast, neither survivin nor survivin splice variants contain an active nuclear import signal and seem to enter the nucleus by passive diffusion. The activity of the NES is required for survivin-mediated protection against cell death inducing stimuli and influences protein degradation. During mitosis, NES-deficient survivin variants fail to correctly localize to the mitotic machinery and promote proper cell division. In vivo and in vitro protein interaction assays show that survivin140 and survivin121 as well as their export-deficient mutants are able to form homo- as well as heterodimers. The trans-dominant negative phenotype observed upon expression of export-deficient survivin appears, therefore, to be mediated by the formation of inactive survivin heterodimers. The survivin-Crm1 axis is essential for the biological activities of murine survivin, and mouse models will allow investigating its functional implications during development and tumorigenesis. © 2006 The Authors Journal compilation.