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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1479-1489.
Prepublished online as a Blood First Edition Paper on October 12, 2006; DOI 10.1182/blood-2006-02-003749.
Previous Article | Next Article 
Submitted February 15, 2006
Accepted October 3, 2006
Dissecting the role of endothelial survivin- Ex3
in angiogenesis
Hugo Caldas, Jason R Fangusaro, Daniel R Boue, Michael P Holloway, and Rachel A Altura*
Center for Childhood Cancer, Columbus Children's Research Institute, Columbus, OH
Center for Biopathology, Columbus Children's Research Institute, Columbus, OH
Dept of Pediatrics, Ohio State University, Columbus, OH
* Corresponding author; email: alturar{at}ccri.net.
The identification of alternative splice variants of Survivin that possess distinct functions from those originally identified for the main Survivin isoform has greatly increased the complexity of our understanding of the role of Survivin in different cells. Previous functional studies of the Survivin splice variants have been performed almost exclusively in cancer cells. However, Survivin has increasingly been implicated in other normal physiologic and pathophysiologic processes, including angiogenesis. In this study we dissect the involvement of Survivin Ex3 in angiogenesis. We show by confocal microscopy that a pool of endothelial Survivin Ex3 is localized to membrane ruffles. We also demonstrate that Survivin Ex3 is the Survivin splice variant responsible for modulating angiogenesis in vitro, in tube formation assays, and in vivo, in an in vivo angiogenesis assay. Our data indicate that Survivin Ex3 may regulate angiogenesis via several mechanisms including cell invasion, migration and Rac1 activation. Our findings identify a novel pathway regulating angiogenesis through Survivin Ex3 and a novel mechanism for Rac1 activation during angiogenesis. In conclusion, our results provide new insights into the regulation of endothelial cell homeostasis and angiogenesis by the Survivin proteins.

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