Survivin is an inhibitor of apoptosis protein that also plays critical roles in regulating the cell cycle and mitosis. Its prominent expression in essentially all human malignancies, and low or absent expression in most normal tissues, suggests that it would be an ideal target for cancerdirected therapy. Impeding development of safe and effective survivin antagonists for clinical use is a lack of understanding of the molecular mechanisms by which survivin differentially affects apoptosis and cell division, in normal and malignant cells. We show that the diverse functional roles of survivin can be explained, in part, by its heterodimerization with survivin splice variants in tumor cells. Survivin and survivin-DEx3 interact within the mitochondria where they may inhibit mitochondrialdependent apoptosis. If the expression of all survivin forms is eliminated by siRNA transfections, cells undergo both apoptosis and defective cell division. Overall, we provide new insights suggesting that targeting specific survivin isoforms, rather than survivin alone, may selectively and effectively destroy tumor cells. These findings are likely to have a significant impact in the design of biologic agents for clinical therapy.

Apoptosis is an essential process during normal neuronal development. Approximately one-half of the neurons produced during neurogenesis die before completion of CNS maturation. To characterize the role of the inhibitor of apoptosis gene, survivin, during neurogenesis, we used the Cre-loxP-system to generate mice lacking survivin in neuronal precursor cells. Conditional deletion of survivin starting at embryonic day 10.5 leads to massive apoptosis of neuronal precursor cells in the CNS. Conditional mutants were born at the expected Mendelian ratios; however, these died shortly after birth from respiratory insufficiency, without primary cardiopulmonary pathology. Newborn conditional mutants showed a marked reduction in the size of the brain associated with severe, mutifocal apoptosis in the cerebrum, cerebellum, brainstem, spinal cord, and retina. Caspase-3 and caspase-9 activities in the mutant brains were significantly elevated, whereas bax expression was unchanged from controls. These results show that survivin is critically required for the survival of developing CNS neurons, and may impact on our understanding of neural repair, neural development, and neurodegenerative diseases. Our study is the first to solidify a role for survivin as an antiapoptotic protein during normal neuronal development in vivo.

Survivin is an apoptotic inhibitor that is expressed at high levels in a variety of malignancies. Survivin has four known alternative splice forms (Survivin, Survivin-2B, Survivin-deltaEx3, and Survivin-3B), and the recent literature suggests that these splice variants have unique functions and subcellular localisation patterns. We evaluated 19 fresh-frozen paediatric medulloblastomas for the expression of three Survivin isoforms by quantitative PCR. Survivin was most highly expressed when compared with normal cerebellar tissue. We also investigated Survivin protein expression in 40 paraffin-embedded paediatric medulloblastoma tumours by immunohistochemistry. We found a statistically significant association between the percentage of Survivin-positive cells and histologic subtype, with the large-cell-anaplastic variant expressing Survivin at higher levels than the classic subtype. We also found a statistically significant relationship between the percent of Survivin-positive cells in the tumours and clinical outcome, with higher levels of Survivin correlating with a worse prognosis. In summary, our study demonstrates a role for Survivin as a marker of tumour morphology and clinical outcome in medulloblastoma. Survivin may be a promising future prognostic tool and potential biologic target in this malignancy.