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Molecular and Cellular Biology, January 2005, p. 250-263, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.250-263.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Novel Intronic cis Element, ISE/ISS-3, Regulates Rat Fibroblast Growth Factor Receptor 2 Splicing through Activation of an Upstream Exon and Repression of a Downstream Exon Containing a Noncanonical Branch Point Sequence

Ruben H. Hovhannisyan and Russ P. Carstens*

Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Received 30 July 2004/ Returned for modification 30 August 2004/ Accepted 28 September 2004

Mutually exclusive splicing of fibroblast growth factor receptor 2 (FGFR2) exons IIIb and IIIc yields two receptor isoforms, FGFR2-IIIb and -IIIc, with distinctly different ligand binding properties. Several RNA cis elements in the intron (intron 8) separating these exons have been described that are required for splicing regulation. Using a heterologous splicing reporter, we have identified a new regulatory element in this intron that confers cell-type-specific inclusion of an unrelated exon that mirrors its ability to promote cell-type-specific inclusion of exon IIIb. This element promoted inclusion of exon IIIb while at the same time silencing exon IIIc inclusion in cells expressing FGFR2-IIIb; hence, we have termed this element ISE/ISS-3 (for "intronic splicing enhancer-intronic splicing silencer 3"). Silencing of exon IIIc splicing by ISE/ISS-3 was shown to require a branch point sequence (BPS) using G as the primary branch nucleotide. Replacing a consensus BPS with A as the primary branch nucleotide resulted in constitutive splicing of exon IIIc. Our results suggest that the branch point sequence constitutes an important component that can contribute to the efficiency of exon definition of alternatively spliced cassette exons. Noncanonical branch points may thus facilitate cell-type-specific silencing of regulated exons by flanking cis elements.

* Corresponding author. Mailing address: University of Pennsylvania School of Medicine, 700 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104-6144. Phone: (215) 573-1838. Fax: (215) 898-0189. E-mail: russcars{at}mail.med.upenn.edu.

Molecular and Cellular Biology, January 2005, p. 250-263, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.250-263.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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