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Molecular and Cellular Biology, September 2008, p. 5403-5419, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00739-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

hnRNP H and hnRNP F Complex with Fox2 To Silence Fibroblast Growth Factor Receptor 2 Exon IIIc{triangledown} ,{dagger}

David M. Mauger,1,2 Carolina Lin,3 and Mariano A. Garcia-Blanco1,2,4*

Department of Molecular Genetics and Microbiology,1 Center for RNA Biology,2 Program in Cell and Molecular Biology,3 Department of Medicine, Duke University Medical Center, Durham, North Carolina 277104

Received 8 May 2008/ Accepted 10 June 2008

The heterogeneous nuclear ribonucleoprotein H (hnRNP) family of proteins has been shown to activate exon inclusion by binding intronic G triplets. Much less is known, however, about how hnRNP H and hnRNP F silence exons. In this study, we identify hnRNP H and hnRNP F proteins as being novel silencers of fibroblast growth factor receptor 2 exon IIIc. In cells that normally include this exon, we show that the overexpression of either hnRNP H1 or hnRNP F resulted in the dramatic silencing of exon IIIc. In cells that normally skip exon IIIc, skipping was disrupted when RNA interference was used to knock down both hnRNP H and hnRNP F. We show that an exonic GGG motif overlapped a critical exonic splicing enhancer, which was predicted to bind the SR protein ASF/SF2. Furthermore, the expression of ASF/SF2 reversed the silencing of exon IIIc caused by the expression of hnRNP H1. We show that hnRNP H and hnRNP F proteins are present in a complex with Fox2 and that the presence of Fox allows hnRNP H1 to better compete with ASF/SF2 for binding to exon IIIc. These results establish hnRNP H and hnRNP F as being repressors of exon inclusion and suggest that Fox proteins enhance their ability to antagonize ASF/SF2.

* Corresponding author. Mailing address: Box 3053 (424 CARL), Duke University Medical Center, Research Drive, Durham, NC 27710. Phone: (919) 613-8632. Fax: (919) 613-8646. E-mail: garci001{at}mc.duke.edu

{triangledown} Published ahead of print on 23 June 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2008, p. 5403-5419, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00739-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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