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

Traffic. 2006 Nov;7(11):1461-72. doi: 10.1111/j.1600-0854.2006.00486.x. Epub 2006 Sep 19.

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 survivin(140), and its splice variants survivin(121) and survivin(40). We show that the dynamic intracellular localization of survivin(140) is mediated by a Crm1-dependent nuclear export signal (NES) present also in survivin(121), but absent in survivin(40). 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 survivin(140) and survivin(121) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Aurora Kinases
  • Caspase 3 / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Chlorocebus aethiops
  • Fatty Acids, Unsaturated / pharmacology
  • Inhibitor of Apoptosis Proteins
  • Karyopherins / antagonists & inhibitors
  • Karyopherins / metabolism
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Mutation / genetics
  • NIH 3T3 Cells
  • Nuclear Export Signals / genetics
  • Nuclear Export Signals / physiology*
  • Nuclear Localization Signals / genetics
  • Nuclear Localization Signals / physiology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins
  • Survivin
  • Transfection
  • Vero Cells

Substances

  • Antibiotics, Antineoplastic
  • Birc5 protein, mouse
  • Fatty Acids, Unsaturated
  • Inhibitor of Apoptosis Proteins
  • Karyopherins
  • Microtubule-Associated Proteins
  • Nuclear Export Signals
  • Nuclear Localization Signals
  • Proteasome Inhibitors
  • Protein Isoforms
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Survivin
  • exportin 1 protein
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Caspase 3
  • Proteasome Endopeptidase Complex
  • leptomycin B