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The Survivin Isoform Survivin-3B is Cytoprotective and can Function as a Chromosomal Passenger Complex Protein

Shirley K. Knauer, Carolin Bier, Peter Schlag, Johannes Fritzmann, Wolfgang Dietmaier, Franz Rödel, Ludger Klein-Hitpass, Adoriàn F. Kovács, Claudia Döring, Martin-Leo Hansmann, Wolf-Karsten Hofmann, Martin Kunkel, Christoph Brochhausen, Knut Engels, Burkhard M. Lippert, Wolf Mann and Roland H. Stauber

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Survivin is described as a bifunctional protein inhibiting apoptosis and regulating mitosis. However, the biological functions and contributions to cancer progression of survivin splice variants are controversially discussed. We here show that the intracellular localization of 5 these splice variants depends on a Crm1-dependent nuclear export signal (NES) present in survivin, survivin-2B and survivin-3B, but absent in survivin-ΔEx3 and survivin-2α. Survivin isoforms lack an active nuclear import signal and are able to enter the nucleus by passive diffusion. Only survivin-3B but none of the other splice variants is cytoprotective and able to efficiently interact with chromosomal passenger complex (CPC) proteins. The NES together 10 with efficient CPC formation is required for the cytoprotective activity of survivin isoforms, as well as for their correct localization and function during cell division. In the tumours from breast, colorectal, head and neck cancer, lymphoma and leukemia patients, survivin and survivin-2B were found overexpressed. However, survivin was the predominant form detected, and the other survivin isoforms were only expressed at low levels in tumours. Our data 15 provide a molecular rationale for the localization and activity of survivin variants, and conclude that survivin isoforms are unlikely to modulate survivin in trans in cancer patients.

Authors

Shirley K. Knauer

University of Mainz, Mainz, Germany

Carolin Bier

University of Mainz, Mainz, Germany

Peter Schlag

Robert-Rössle Clinic, Berlin, Germany

Johannes Fritzmann

Robert-Rössle Clinic, Berlin, Germany

Wolfgang Dietmaier

Unviersity of Regensburg, Regensburg, Germany

Franz Rödel

University Hospital of Frankfurt, Frankfurt, Germany

Ludger Klein-Hitpass

University Hospital of Essen, Essen, Germany

Adoriàn F. Kovács

University Hospital of Frankfurt, Frankfurt, Germany

Claudia Döring

University of Frankfurt, Frankfurt, Germany

Martin-Leo Hansmann

University of Frankfurt, Frankfurt, Germany

Wolf-Karsten Hofmann

University Hospital Berlin, Berlin, Germany

Martin Kunkel

University Hospital of Mainz, Mainz, Germany

Christoph Brochhausen

University of Mainz, Mainz, Germany

Knut Engels

University of Frankfurt, Frankfurt, Germany

Burkhard M. Lippert

University Hospital of Mainz, Mainz, Germany

Wolf Mann

University of Mainz, Mainz, Germany

Roland H. Stauber

University of Mainz, Mainz, Germany

Purchase article for $19

Subscribe to this journal for $129/year