title: 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/Delta)(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/Delta)(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/Delta)(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.
authors.affiliation: Respiratory Cell and Molecular Biology Laboratory, Division of Molecular and Genetic Medicine, The University of Sheffield Medical School, Sheffield, S10 2RX, United Kingdom. c.d.bingle@sheffield.ac.uk
authors.forename: C D
authors.initials: CD
authors.lastname: Bingle
authors.forename: R W
authors.initials: RW
authors.lastname: Craig
authors.forename: B M
authors.initials: BM
authors.lastname: Swales
authors.forename: V
authors.initials: V
authors.lastname: Singleton
authors.forename: P
authors.initials: P
authors.lastname: Zhou
authors.forename: M K
authors.initials: MK
authors.lastname: Whyte
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D006801:Humans; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2