title: Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.
abstract: The Foxp subfamily of forkhead/HNF3 transcription factors has recently been recognized because of its involvement in autoimmune disease, speech and language disorders, and lung development. Domains unique to this subfamily include a divergent DNA-binding winged helix, a leucine zipper, a zinc finger, and a polyglutamine tract. Little is known about the properties of these proteins that are fundamental to their function as transcription factors nor how the Foxp sequence motifs regulate their transcriptional regulatory properties. We report here a structure/function analysis of the Foxp1 protein. We have analyzed the alternative splice isoforms 1A and 1C and also report the cloning and characterization of a novel isoform Foxp1D that lacks the polyglutamine domain. We have isolated the preferred DNA-binding sites for Foxp1 transcription factors. Foxp1A, C, and D isoforms and the related Foxp2 protein repress gene transcription via binding to this consensus site or to a naturally occurring site within the SV40 and the interleukin-2 promoters. In some cases the strength of Foxp1 repression is mediated by the polyglutamine domain. Unlike previously characterized forkhead factors, Foxp1 proteins can form homodimers or heterodimers with subfamily members. The dimerization domain was localized to an evolutionarily conserved C2H2 zinc finger and leucine zipper motif. Finally, we demonstrate that Foxp1, although broadly expressed, is further regulated by tissue-specific alternative splicing of these functionally important sequence domains. These results suggest that Foxp1 proteins have diverse functional roles in different cell and tissue types.
authors.affiliation: Department of Molecular Genetics and the Institute for Cellular and Molecular Biology, University of Texas, Austin 78712-0162, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Danjuan
authors.initials: D
authors.lastname: Lin
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
authors.forename: Philip
authors.initials: P
authors.lastname: Tucker
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D019281:Dimerization; D051858:Forkhead Transcription Factors; D006801:Humans; D008969:Molecular Sequence Data; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D012097:Repressor Proteins