title: Antagonistic regulation of alpha-actinin alternative splicing by CELF proteins and polypyrimidine tract binding protein.
abstract: The alpha-actinin gene has a pair of alternatively spliced exons. The smooth muscle (SM) exon is repressed in most cell types by polypyrimidine tract binding protein (PTB). CELF (CUG-BP and ETR3-like factors) family proteins, splicing regulators whose activities are altered in myotonic dystrophy, were found to coordinately regulate selection of the two alpha-actinin exons. CUG-BP and ETR3 activated the SM exon, and along with CELF4 they were also able to repress splicing of the NM (nonmuscle) exon both in vivo and in vitro. Activation of SM exon splicing was associated with displacement of PTB from the polypyrimidine tract by binding of CUG-BP at adjacent sites. Our data provides direct evidence for the activity of CELF proteins as both activators and repressors of splicing within a single-model system of alternative splicing, and suggests a model whereby alpha-actinin alternative splicing is regulated by synergistic and antagonistic interactions between members of the CELF and PTB families.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gromak
authors.forename: Arianne J
authors.initials: AJ
authors.lastname: Matlin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
authors.forename: Christopher W J
authors.initials: CW
authors.lastname: Smith
mesh_terms: D000185:Actinin / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D000067878:CELF Proteins; D000067879:CELF1 Protein; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism*; D012322:RNA Precursors / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D000067878:CELF Proteins; D000067879:CELF1 Protein; C102843:CELF1 protein, human; C117363:CELF2 protein, human; C422243:CELF4 protein, human; D009419:Nerve Tissue Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D000185:Actinin; D038941:Polypyrimidine Tract-Binding Protein