Exon Skipping in Mcl-1 Results in a Bcl-2 Homology Domain 3 Only Gene Product That Promotes Cell Death*

Abstract

Mcl-1 is a member of the Bcl-2 family that is regulated transcriptionally and post-transcriptionally, with expression of the full-length Mcl-1-encoded gene product resulting in enhanced cell survival. As reported here, the human Mcl-1 gene can also undergo differential splicing, which yields an internally deleted, death-inducing gene product, Mcl-1_{s/Δ TM}. Whereas full-length Mcl-1 derives from three coding exons (instead of the two present in Bcl-2 and other anti-apoptotic members of this family), the Mcl-1_{s/Δ TM} splice variant results from the joining of the first and third exons with skipping of the central exon. Because of the skipped exon and a shift in the reading frame downstream, the Bcl-2 homology domain (BH3) remains intact, whereas the BH1-, BH2-, and transmembrane-encoding domains do not. Mcl-1_{s/Δ TM} thus has features similar to BH3 only, pro-apoptotic Bcl-2 family members and, accordingly, was found to promote cell death. In addition to a variety of other types of regulation, the Mcl-1 gene appears ideally designed for the generation of either a Bcl-2-like viability promoting or, as reported here, a BH3 only death-inducing gene product.