The survivin isoform survivin-3B is cytoprotective and can function as a chromosomal passenger complex protein

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 these splice variants depends on a Crm1-dependent nuclear export signal (NES) present in survivin, surviving(-2B) and survivin(-3B), but absent in survivin(-deltaEx3) and survivin(-2alpha). 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 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 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.