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J. Biol. Chem., Vol. 283, Issue 15, 10058-10067, April 11, 2008

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Identification of an Intronic Splicing Enhancer Essential for the Inclusion of FGFR2 Exon IIIc^*

Puneet Seth¹, Heather B. Miller, Erika L. Lasda², James L. Pearson, and Mariano A. Garcia-Blanco^¶3

From the Departments of Molecular Genetics and Microbiology and ^¶Medicine and the Center for RNA Biology, Duke University Medical Center, Durham, North Carolina 27710

The ligand specificity of fibroblast growth factor receptor 2 (FGFR2) is determined by the alternative splicing of exons 8 (IIIb) or 9 (IIIc). Exon IIIb is included in epithelial cells, whereas exon IIIc is included in mesenchymal cells. Although a number of cis elements and trans factors have been identified that play a role in exon IIIb inclusion in epithelium, little is known about the activation of exon IIIc in mesenchyme. We report here the identification of a splicing enhancer required for IIIc inclusion. This 24-nucleotide (nt) downstream intronic splicing enhancer (DISE) is located within intron 9 immediately downstream of exon IIIc. DISE was able to activate the inclusion of heterologous exons rat FGFR2 IIIb and human β-globin exon 2 in cell lines from different tissues and species and also in HeLa cell nuclear extracts in vitro. DISE was capable of replacing the intronic activator sequence 1 (IAS1), a known IIIb splicing enhancer and vice versa. This fact, together with the requirement for DISE to be close to the 5'-splice site and the ability of DISE to promote binding of U1 snRNP, suggested that IAS1 and DISE belong to the same class of cis-acting elements.

Received for publication, January 4, 2008

^* This work was supported in part by National Institutes of Health Grant R01 GM63090 (to M. A. G. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Present address: 4043 Purple Zone, Division of Dermatology, Duke University Medical Center.

² Present address: Molecular, Cellular, and Developmental Biology, 347 UCB, University of Colorado, Boulder, CO 80309-0347.

³ To whom correspondence should be addressed: Box 3053 (424 CARL), Duke University Medical Center, Research Dr., Durham, NC 27710. Tel.: 919-613-8632; Fax: 919-613-8646; E-mail: garci001{at}mc.duke.edu.

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