Survivin 2α: a novel Survivin splice variant expressed in human malignancies

In the present study, we identify and characterize a novel survivin isoform that we designate survivin 2α. Structurally, the transcript consists of 2 exons: exon 1 and exon 2, as well as a 3' 197 bp region of intron 2. Acquisition of a new in-frame stop codon within intron 2 results in an open reading frame of 225 nucleotides, predicting a truncated 74 amino acid protein. Survivin 2α is expressed at high levels in several malignant cell lines and primary tumors. Functional assays show that survivin 2α attenuates the anti-apoptotic activity of survivin. Subcellular localization and immunoprecipitation of survivin 2α suggests a physical interaction with survivin.We characterized a novel survivin splice variant that we designated survivin 2α. We hypothesize that survivin 2α can alter the anti-apoptotic functions of survivin in malignant cells. Thus survivin 2α may be useful as a therapeutic tool in sensitizing chemoresistant tumor cells to chemotherapy.Alternative splicing is estimated to occur in 40–60% of all human genes, accounting for some of the discrepancies between the large number of known proteins and the three-fold lower number of human genes in the genome. Alternative splicing generates a multitude of isoforms that have overlapping but distinct functions during embryonic development and that also contribute to maintaining homeostasis in adult differentiated tissues (reviewed in [1]). Alternative splice forms of key proteins in cancer, TP53, MDM2 [2] and c-MYC [3], have been shown to play a role in oncogenesis.Survivin was originally identified by structural homology to IAPs in human B-cell lymphoma [4]. It is composed of a single BIR domain and an extended carboxy-terminal coiled coil domain [5]. Transcription from the Survivin locus gives rise to alternatively spliced transcripts identified in both human and mice [6-8]. To date, three alternatively spliced isoforms have been described in humans [6-8]. Survivin-2B is generated by the insertion of an alternat