Nuclear export is essential for the tumor-promoting activity of survivin.
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.
Knauer
Shirley K
SK
Georg-Speyer-Haus Institute for Biomedical Research, Paul-Ehrlich-Str. 42-44, D-60596 Frankfurt, Germany.
Krämer
Oliver H
OH
Knösel
Thomas
T
Engels
Knut
K
Rödel
Franz
F
Kovács
Adorján F
AF
Dietmaier
Wolfgang
W
Klein-Hitpass
Ludger
L
Habtemichael
Negusse
N
Schweitzer
Andrea
A
Brieger
Jürgen
J
Rödel
Claus
C
Mann
Wolf
W
Petersen
Iver
I
Heinzel
Thorsten
T
Stauber
Roland H
RH
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
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