Survivin-ΔEx3 and Survivin-2B: Two Novel Splice Variants of the Apoptosis Inhibitor Survivin with Different Antiapoptotic Properties

Abstract

Recently, a novel antiapoptosis gene, i.e., survivin, was identified as a structurally unique member of the inhibitor of apoptosis protein family. Survivin expression is turned off during fetal development and not found in non-neoplastic adult human tissues but is again turned on in the most common human cancers. The antiapoptotic properties of survivin might provide a significant growth advantage in tumors and possibly also contribute to chemoresistance of cancer. Therefore, we analyzed the expression of survivin in human renal cell carcinomas (RCCs), known to be largely resistant to chemotherapy. Northern blot analysis and RT-PCR revealed survivin expression in newly established RCC cell lines (n = 11) of all major histological types. Moreover, we identified two novel splice variants of survivin, lacking exon 3 (survivin-ΔEx3) or retaining a part of intron 2 as a cryptic exon (survivin-2B). Both sequence alterations cause marked changes in the structure of the corresponding proteins, including structural modifications of the baculovirus inhibitor of apoptosis protein repeat domain. The role of the novel isoforms in the regulation of apoptosis was assessed in transfection experiments, showing conservation of antiapoptotic properties for survivin-ΔEx3 and a markedly reduced antiapoptotic potential for survivin-2B. In conclusion, our observations suggest a complex regulatory balance between the different isoforms of survivin, which might determine the response to proapoptotic stimuli, not only in human RCCs but also in fetal tissues and other types of cancer.