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Nuclear export is essential for the tumor-promoting activity of survivin

Shirley K. Knauer^*, Oliver H. Krämer, Thomas Knösel, Knut Engels, Franz Rödel^||, Adorján F. Kovács^¶, Wolfgang Dietmaier^**, Ludger Klein-Hitpass, Negusse Habtemichael^*, Andrea Schweitzer^*, Jürgen Brieger, Claus Rödel^||, Wolf Mann, Iver Petersen, Thorsten Heinzel and Roland H. Stauber^*,1

^* Georg-Speyer-Haus, Institute for Biomedical Research, Frankfurt, Germany;

Institute of Biochemistry and Biophysics, University of Jena, Jena, Germany;

Institute of Pathology, Charité-CCM, Medical Faculty Humboldt-University Berlin, Berlin, Germany;

Department of Pathology, University Hospital of Frankfurt, Frankfurt, Germany;

^|| Department of Radiation Oncology, University of Erlangen-Nuremberg, Erlangen, Germany;

^¶ Maxillofacial Plastic Surgery, University Hospital of Frankfurt, Germany;

^** Institute of Pathology, University of Regensburg, Regensburg, Germany;

Institute for Cell Biology, University Hospital of Essen, Essen, Germany; and

Department of Otorhinolaryngology, University Hospital of Mainz, Mainz, Germany

¹Correspondence: Georg-Speyer-Haus Institute for Biomedical Research, Paul-Ehrlich-Str. 42–44, D-60596 Frankfurt, Germany. E-mail: stauber{at}em.uni-frankfurt.de

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, S. K., Krämer, O. H., Knösel, T., Engels, K., Rödel, F., Kovács, A. F., Dietmaier, W., Klein-Hitpass, L., Habtemichael, N., Schweitzer, A., Brieger, J., Rödel, C., Mann, W., Petersen, I., Heinzel, T., Stauber, R. H. Nuclear export is essential for the tumor-promoting activity of survivin.

Key Words: nucleocytoplasmic transport • apoptosis • Crm1 • head and neck cancer • colorectal cancer • cancer therapy • LMB • cisplatin • valproic acid • HDAC

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