Three differentially expressed survivin cDNA variants encode proteins with distinct antiapoptotic functions

Abstract

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 murinesurvivin 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.

Protective role of the inhibitor of apoptosis protein, survivin, in toxin‐induced acute renal failure

“…The cDNAs encoding full-length murine survivin (survivin 140 ), survivin 121 , and survivin 40 (36) were each cloned into the expression vector pcDNA3 (Invitrogen, San Diego, CA, USA), resulting in the vectors survivin 140 /pcDNA3, survivin 121 /pcDNA3, and survivin 40 /pcDNA3. For in vivo gene delivery, 25 or 50 g plasmid DNA in 2 ml of saline or Ringer solution was injected in 5-6 s via the tail vein of mice (37,38).…”

“…We have previously reported that, in the mouse, there are three distinct survivin mRNAs that encode functionally distinct proteins (36). Both survivin 140 (the full-length form) and survivin 121 retain the BIR domain that is crucial for interfering with caspase activation, whereas survivin 121 lacks the C-terminal coiled-coil domain, which functionally links survivin to the cell cycle (44).…”

Aberrant expression of caspase cascade regulatory genes in adult T‐cell leukaemia: survivin is an important determinant for prognosis

“…Presently, SV as an unique apoptosis inhibitor (Ambrosini et al, 1997) is believed to play a role in oncogenesis (Conway et al, 2000). This is because SV expression is switched off during fetal development and not found in non-neoplastic adult human tissues, while it is prominently re-expressed by all the most common human cancers, including carcinomas of lung, stomach, colon and breast as well as high grade non-Hodgkin's lymphoma.…”

“…This discrepancy between in vivo and in vitro suggests that inhibitors of downstream components in the Fas signalling pathway (caspase cascade) regulate the signal transduction, because upregulated Fas expressed by ATL cells is usually wild and functional . Indeed, evidence is now accumulating that Fas-mediated signalling is regulated by inhibitory proteins, such as Fas-associated phosphatase-1 (FAP-1) (Seto et al, 1995;Komada et al, 1997), FLICE-inhibitory proteins (FLIP) (Goltsev et al, 1997;Tepper & Seldin, 1999), survivin (SV) (Ambrosini et al, 1997) and splicing variants of casp-8, which is competitive against splicing the intact form of casp-8 (Boldin et al, 1996;Horiuchi et al, 2000). Subsequently, tumour biology may be influenced by expression levels of the inhibitors, facilitating the insurgence of mutations and promoting resistance to therapy.…”

Human inhibitor of apoptosis protein (IAP)survivinparticipates in regulation of chromosome segregation and mitotic exit

“…A recent discovery of multiple human and murine survivin isoforms perhaps explains the different mitotic effects induced by survivin targeting (17). In both species, three differentially expressed survivin cDNAs with predicted isoform size of 140-, 120-and 40-amino acid residues have been identified, which suggests that survivin isoforms may play multiple roles in the regulation of apoptosis and cell division in mammals ( Fig.…”