Bax 2 Family Alternative Splicing Salvages Bax Microsatellite-Frameshift Mutations

Mutation or aberrant splicing can interrupt gene expression. Tumor suppressor Bax is one of the susceptible genes prone to microsatellite frameshifting mutations in coding regions. As a result, tumors exhibiting microsatellite instability (MSI) often present a "Bax-negative" phenotype. We previously reported that some Bax-negative cells in fact contain a functional Bax isoform (BaxΔ2), generated when unique alternative splicing "salvages" the shifted reading frame introduced by a microsatellite mutation. Here we compared Bax alternative splicing profiles in a range of cell lines and primary tumors with and without Bax microsatellite mutations. We found that MSI tumors exhibit a high Bax alternative splicing frequency, especially in exon 2, and produce a family of alternatively spliced isoforms that retain many important Bax functional domains. Surprisingly, these BaxΔ2 family isoforms can rescue Bax from all common microsatellite frameshift mutations. Production of BaxΔ2 requires specific cis mutations, while trans components are not cell-type specific. Furthermore, all BaxΔ2 family isoforms are more potent cell death inducers than the parental Bax without directly targeting mitochondria. These results indicate that the BaxΔ2 family can potentially salvage Bax tumor suppressor expression otherwise lost to mutation.