Tissue-specific splicing regulator Fox-1 induces exon skipping by interfering E complex formation on the downstream intron of human F1gamma gene.
Fox-1 is a regulator of tissue-specific splicing, via binding to the element (U)GCAUG in mRNA precursors, in muscles and neuronal cells. Fox-1 can regulate splicing positively or negatively, most likely depending on where it binds relative to the regulated exon. In cases where the (U)GCAUG element lies in an intron upstream of the alternative exon, Fox-1 protein functions as a splicing repressor to induce exon skipping. Here we report the mechanism of exon skipping regulated by Fox-1, using the hF1gamma gene as a model system. We found that Fox-1 induces exon 9 skipping by repressing splicing of the downstream intron 9 via binding to the GCAUG repressor elements located in the upstream intron 8. In vitro splicing analyses showed that Fox-1 prevents formation of the pre-spliceosomal early (E) complex on intron 9. In addition, we located a region of the Fox-1 protein that is required for inducing exon skipping. Taken together, our data show a novel mechanism of how RNA-binding proteins regulate alternative splicing.
Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodaicho, Nadaku, Kobe 657-8501, Japan.
Kazuhiro
K
Fukumura
Ayako
A
Kato
Yui
Y
Jin
Takashi
T
Ideue
Tetsuro
T
Hirose
Naoyuki
N
Kataoka
Toshinobu
T
Fujiwara
Hiroshi
H
Sakamoto
Kunio
K
Inoue
D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005091:Exons; D006801:Humans; D007438:Introns; D051379:Mice; D009132:Muscles / Q000378:metabolism; D017434:Protein Structure, Tertiary; D006180:Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D012322:RNA Precursors / Q000737:chemistry / Q000378:metabolism; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000378:metabolism; D017381:Spliceosomes / Q000378:metabolism*
D012322:RNA Precursors; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C465036:Rbfox1 protein, mouse; D012097:Repressor Proteins; C444660:gamma subunit, F(1) ATPase; D006180:Proton-Translocating ATPases