Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1435-1442
Three differentially expressed survivin cDNA variants
encode proteins with distinct antiapoptotic functions
Edward M. Conway,
Saskia Pollefeyt,
Jan Cornelissen,
Inky DeBaere,
Marta Steiner-Mosonyi,
Kelly Ong,
Mathijs Baens,
Désiré Collen, and
Andre C. Schuh
From the Departments of Medicine and the Institute of Medical
Science, University of Toronto, Toronto, Canada; Center for Transgene
Technology and Gene Therapy; Department of Human Genetics, Flanders
Interuniversity Institute for Biotechnology, University of Leuven,
Leuven, Belgium.
Survivin is a member of the inhibitor of apoptosis protein (IAP)
family that is believed to play a role in oncogenesis. To elucidate
further its physiologic role(s), we have characterized the murine
survivin gene and complementary DNA (cDNA). The structural organization of the survivin gene, located on chromosome 11E2, is similar to that of its human counterpart, both containing 4 exons.
Surprisingly, 3 full-length murine survivin cDNA clones were
isolated, predicting the existence of 3 distinct survivin proteins. The
longest open reading frame, derived from all 4 exons, predicts a
140-amino acid residue protein, survivin140, similar to
human survivin, which contains a single IAP repeat and a COOH-terminal coiled-coil domain that links its function to the cell cycle. A second
cDNA, which retains intron 3, predicts the existence of a 121-amino
acid protein, survivin121 that lacks the coiled-coil domain. Removal of exon 2-derived sequences by alternative
pre-messenger RNA (mRNA) splicing results in a third 40-amino acid
residue protein, survivin40, lacking the IAP repeat and
coiled-coil structure. Predictably, only recombinant
survivin140 and survivin121 inhibited caspase-3
activity. All 3 mRNA species were variably expressed during development
from 7.5 days postcoitum. Of the adult tissues surveyed, thymus and
testis accumulated high levels of survivin140 mRNA, whereas
survivin121-specific transcripts were detected in all
tissues, while those representing survivin40 were absent. Human counterparts to the 3 survivin mRNA transcripts were identified in a study of human cells and tissues. The presence of distinct isoforms of survivin that are expressed differentially suggests that
survivin plays a complex role in regulating apoptosis.
