Fox-2 splicing factor binds to a conserved intron motif to promote inclusion of protein 4.1R alternative exon 16
Open accessAbstract
Activation of protein 4.1R exon 16 (E16) inclusion during erythropoiesis represents a physiologically important splicing switch that increases 4.1R affinity for spectrin and actin. Previous studies showed that negative regulation of E16 splicing is mediated by the binding of heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins to silencer elements in the exon and that down-regulation of hnRNP A/B proteins in erythroblasts leads to activation of E16 inclusion. This article demonstrates that positive regulation of E16 splicing can be mediated by Fox-2 or Fox-1, two closely related splicing factors that possess identical RNA recognition motifs. SELEX experiments with human Fox-1 revealed highly selective binding to the hexamer UGCAUG. Both Fox-1 and Fox-2 were able to bind the conserved UGCAUG elements in the proximal intron downstream of E16, and both could activate E16 splicing in HeLa cell co-transfection assays in a UGCAUG-dependent manner. Conversely, knockdown of Fox-2 expression, achieved with two different siRNA sequences resulted in decreased E16 splicing. Moreover, immunoblot experiments demonstrate mouse erythroblasts express Fox-2. These findings suggest that Fox-2 is a physiological activator of E16 splicing in differentiating erythroid cells in vivo. Recent experiments show that UGCAUG is present in the proximal intron sequence of many tissue-specific alternative exons, and we propose that the Fox family of splicing enhancers plays an important role in alternative splicing switches during differentiation in metazoan organisms.
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Rbfox proteins bind the (U)GCAUG element, which is frequently conserved across vertebrates.
“Rbfox proteins are known as tissue-specific splicing factors which bind to the (U)GCAUG element frequently conserved across vertebrate species (Jin et al., 2003; Minovitsky et al., 2005; Ponthier et al., 2006; Underwood et al., 2005).”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Ponthier et al., 2006
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- Authors
- Ponthier, J. L., Schluepen, C., Chen, W., Lersch, R. A., Gee, S. L., Hou, V. C., Lo, A. J., Short, S. A., Chasis, J. A., Winkelmann, J. C., & Conboy, J. G.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- University of Cincinnati (US)
- Corresponding author
- Conboy, John G.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 281
- Issue
- 18
- Pages
- 12468-12474
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1514379483
- Cited by
- 0
- References
- 50
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- University of North Texas Digital Library (University of North Texas) (submittedVersion)
- Lawrence Berkeley National Laboratory
- Funders
- Deutsche Forschungsgemeinschaft (DE-AC03-76SF00098)
- National Institutes of Health (DE-AC03- 76SF00098, DK32094)
- National Heart, Lung, and Blood Institute (R01HL045182, HL45182)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK032094, DK32094)
- Biological and Environmental Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- protein 4.1R, exon 16, alternative splicing, splicing enhancers, erythropoiesis, erythroblasts, hnRNP A/B, RNA recognition motif, SELEX, cell differentiation
- MeSH terms
- RNA Splicing Factors, Base Sequence, Blood Proteins, Cell Differentiation, Cytoskeletal Proteins, DNA-Binding Proteins, Erythroblasts, Exons, Gene Expression Regulation, HeLa Cells, Humans, Introns, Membrane Proteins, Microtubule-Associated Proteins, Molecular Sequence Data, Repressor Proteins, Transcription Factors, Down-Regulation, RNA-Binding Proteins, Amino Acid Motifs, Heterogeneous-Nuclear Ribonucleoproteins, RNA, Small Interfering
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