Analysis of the functional repertoire of a mutant form of survivin, K129E, which has been linked to lung cancer

Abstract

BackgroundSurvivin is a protein that is normally present only in G2 and M-phases in somatic cells, however, in cancer cells, it is expressed throughout the cell cycle. A prosurvival factor, survivin is both an inhibitor of apoptosis and an essential mitotic protein, thus it has attracted much attention as a target for new oncotherapies. Despite its prevalence in cancer, reports of survivin mutations have mostly been restricted to loci within its promoter, which increase the abundance of the protein. To date the only published mutation within the coding sequence is an adenine > guanine substitution in exon 4. This polymorphism, which was found in a cohort of Korean lung cancer patients, causes a lysine > glutamic acid mutation (K129E) in the protein. However, whether it plays a causative role in cancer has not been addressed.MethodsUsing site directed mutagenesis we recapitulate K129E expression in cultured human cells and assess its anti-apoptotic and mitotic activities.ResultsK129E retains its anti-apoptotic activity, but causes errors in mitosis and cytokinesis, which may be linked to its reduced affinity for borealin.ConclusionK129E expression can induce genomic instability by introducing mitotic aberrations, thus it may play a causative role in cancer.

Mitotic activity of survivin is regulated by acetylation at K129

“…15 However, in marked contrast to K129E, both K129A and K129R bind avidly to borealin, eliminating the possibility that this biochemical interaction is the reason for compromising genomic integrity. Given that stability is impaired, it is possible that interaction with other non-mitotic partner, such as XIAP, 31 are accountable for this response.…”

“…While positioned at the centromere, survivin is also bound to borealin, which is a direct interaction involving its C-terminal a helix, and which we found to be abrogated when K129 was substituted for glutamic acid. 15 In this regard we asked whether interaction with borealin was affected by A or R substitutions of K129. However, both K129A and K129R bound borealin avidly when co-immunoprecipitates from DMA treated cultures were examined with anti-borealin antibodies (Fig.…”

“…15 As K129E was originally identified as a single nucleotide polymorphism in a cohort of lung cancer patients, 16 and its expression leads to genomic instability, it seemed prudent to investigate whether modification of this site by acetylation compromises survivin function. We have therefore expressed an acetyl-mimetic (K129A) version of survivin in HeLa cells and monitored the effects on cell division using fluorescence imaging, and compared them with those of cells in which global acetylation has been maintained with the deacetylase inhibitor, trichostatin A (TSA).…”

Survivin at a glance

“…Although many single-nucleotide polymorphisms (SNPs) have been found in its promoter, mutations within the gene coding region are rare, but one that has been reported is a lysine to glutamic acid mutation, K129E (Jang et al, 2008). When assessed in cultured cells, the K129E variant caused mitotic defects by decreasing the affinity of survivin to borealin (Aljaberi et al, 2014). Clearly, with roles in mitosis, apoptosis suppression, autophagy, migration, metabolism and angiogenesis, there are many routes through which survivin can promote tumour cell survival and cancer metastasis.…”

Sequence Characterization of Baculoviral Inhibitor of Apoptosis Repeat Containing 5 (BIRC 5) Gene from a Case of Canine Mammary Tumour

“…The gene is thoroughly studied in humans and several polymorphisms have been detected in the promoter region of survivin gene. But most of the mutation studies in humans are restricted within the promoter region of survivn gene and to date, there is a single report of mutation within the coding region of the gene, i.e., lysine>glutamic acid (K129E) mutation in the exon 4 of the protein (Aljaberi et al, 2014). Despite the prevalence of survivin in dog cancers, no studies have been conducted so far in dogs to find out any mutations in the coding region or the promoter region of survivin gene and correlation of such alterations with changes in gene expression in cases of dog cancers.…”