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Nucleic Acids Research 2006 34(1):373-385; doi:10.1093/nar/gkj407
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Published online 12 January 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
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Article

Characterization of sequences and mechanisms through which ISE/ISS-3 regulates FGFR2 splicing

Ruben H. Hovhannisyan1, Claude C. Warzecha2 and Russ P. Carstens1,2,*

1Department of Medicine, University of Pennsylvania School of Medicine 700 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104, USA 2Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine 700 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104, USA

*To whom correspondence should be addressed. Tel: +1 215 573 1838; Fax: +1 215 898 0189; Email: russcars{at}mail.med.upenn.edu

Received October 28, 2005. Revised December 5, 2005. Accepted December 5, 2005.

Alternative splicing of fibroblast growth factor receptor-2 (FGFR2) mutually exclusive exons IIIb and IIIc results in highly cell-type-specific expression of functionally distinct receptors, FGFR2-IIIb and FGFR2-IIIc. We previously identified an RNA cis-element, ISE/ISS-3, that enhanced exon IIIb splicing and silenced exon IIIc splicing. Here, we have performed comprehensive mutational analysis to define critical sequence motifs within this element that independently either enhance splicing of upstream exons or repress splicing of downstream exons. Such analysis included use of a novel fluorescence-based splicing reporter assay that allowed quantitative determination of relative functional activity of ISE/ISS-3 mutants using flow cytometric analysis of live cells. We determined that specific sequences within this element that mediate splicing enhancement also mediate splicing repression, depending on their position relative to a regulated exon. Thus, factors that bind the element are likely to be coordinately involved in mediating both aspects of splicing regulation. Exon IIIc silencing is dependent upon a suboptimal branchpoint sequence containing a guanine branchpoint nucleotide. Previous studies of exon IIIc splicing in HeLa nuclear extracts demonstrated that this guanine branchsite primarily impaired the second step of splicing suggesting that ISE/ISS-3 may block exon IIIc inclusion at this step. However, results presented here that include use of newly developed in vitro splicing assays of FGFR2 using extracts from a cell line expressing FGFR2-IIIb strongly suggest that cell-type-specific silencing of exon IIIc occurs at or prior to the first step of splicing.


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