title: Nuclear export is essential for the tumor-promoting activity of survivin.
abstract: Survivin appears to function as an apoptosis inhibitor and a regulator of cell division during development and tumorigenesis. Here we report the molecular characterization of the nucleocytoplasmic transport of survivin and its potential implications for tumorigenesis. We identified an evolutionary conserved Crm1-dependent nuclear export signal (NES) in survivin. In dividing cells, the NES is essential for tethering survivin and the survivin/Aurora-B kinase complex to the mitotic machinery, which in turn appears to be essential for proper cell division. In addition, export seems to be required for the cytoprotective activity of survivin, as export-deficient survivin fails to protect tumor cells against chemo- and radiotherapy-induced apoptosis. These findings appear to be clinically relevant since preferential nuclear localization of survivin correlated with enhanced survival in colorectal cancer patients. Targeting survivin's nuclear export by the application of NES-specific antibodies promoted its nuclear accumulation and inhibited its cytoprotective function. We demonstrate that nuclear export is essential for the biological activity of survivin and promote the identification of molecular decoys to specifically interfere with survivin's nuclear export as potential anticancer therapeutics.
authors.affiliation: Georg-Speyer-Haus Institute for Biomedical Research, Paul-Ehrlich-Str. 42-44, D-60596 Frankfurt, Germany.
authors.forename: Shirley K
authors.initials: SK
authors.lastname: Knauer
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
authors.forename: Thomas
authors.initials: T
authors.lastname: Knösel
authors.forename: Knut
authors.initials: K
authors.lastname: Engels
authors.forename: Franz
authors.initials: F
authors.lastname: Rödel
authors.forename: Adorján F
authors.initials: AF
authors.lastname: Kovács
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Negusse
authors.initials: N
authors.lastname: Habtemichael
authors.forename: Andrea
authors.initials: A
authors.lastname: Schweitzer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brieger
authors.forename: Claus
authors.initials: C
authors.lastname: Rödel
authors.forename: Wolf
authors.initials: W
authors.lastname: Mann
authors.forename: Iver
authors.initials: I
authors.lastname: Petersen
authors.forename: Thorsten
authors.initials: T
authors.lastname: Heinzel
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stauber
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology* / Q000532:radiotherapy; D017931:DNA Primers; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism* / Q000502:physiology; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000502:physiology; D049790:Nuclear Export Signals; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000077022:Survivin; D000097606:Exportin 1 Protein
chemical_list: D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D049790:Nuclear Export Signals; D018160:Receptors, Cytoplasmic and Nuclear; D000077022:Survivin; D000097606:Exportin 1 Protein; C107489:BIRC5 protein, human