Three differentially expressed survivin cDNA variants encode proteins withdistinct antiapoptotic functions

Survivin is a member of the inhibitor of apoptosis protein (IAP) family tha t is believed to play a role in oncogenesis, To elucidate further its physi ologic role(s), we have characterized the murine survivin gene and compleme ntary DNA (cDNA). The structural organization of the survivin gene, located on chromosome 11E2, is similar to that of its human counterpart, both cont aining 4 exons, Surprisingly, 3 full-length murine survivin cDNA clones wer e isolated, predicting the existence of 3 distinct survivin proteins, The l ongest open reading frame, derived from all 4 exons, predicts a 140-amino a cid residue protein, survivin(140), similar to human survivin, which contai ns a single IAP repeat and a COOH-terminal coiled-coil domain that links it s function to the cell cycle. A second cDNA, which retains intron 3, predic ts the existence of a 121-amino acid protein, survivin(121) that lacks the coiled-coil domain. Removal of exon P-derived sequences by alternative prem essenger RNA (mRNA) splicing results in a third 40-amino acid residue prote in, survivin(40), lacking the IAP repeat and coiled-coil structure, Predict ably, only recombinant survivin(140) and survivin(121) inhibited caspase-3 activity, All 3 mRNA species were variably expressed during development fro m 7.5 days postcoitum. Of the adult tissues surveyed, thymus and testis acc umulated high levels of survivin(140) mRNA, whereas survivin(121)-specific transcripts were detected in all tissues, while those representing survivin (40) were absent. Human counterparts to the 3 survivin mRNA transcripts wer e identified in a study of human cells and tissues. The presence of distinc t isoforms of survivin that are expressed differentially suggests that surv ivin plays a complex role in regulating apoptosis. (C) 2000 by The American Society of Hematology.