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An Exonic Splicing Enhancer in Human IGF-I Pre-mRNA Mediates Recognition of Alternative Exon 5 by the Serine-Arginine Protein Splicing Factor-2/ Alternative Splicing Factor

Department of Endocrinology (P.J.S., E.L.S., R.J.M.R., S.L.C.), and Department of Anaesthesia and Intensive Care (J.C., C.J.H.), St. Bartholomew’s Hospital, Queen Mary, University of London, London EC1A 7BE, United Kingdom; and Cold Spring Harbor Laboratory (A.R.K.), Cold Spring Harbor, New York 11724

Address all correspondence and requests for reprints to: Shern L. Chew, Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom. E-mail: s.l.chew{at}mds.qmw.ac.uk

The human IGF-I gene has six exons, four of which are alternatively spliced. Variations in splicing involving exon 5 may occur, depending on the tissue type and hormonal environment. To study the regulation of splicing to IGF-I exon 5, we established an in vitro splicing assay, using a model pre-mRNA containing IGF-I exons 4 and 5 and part of the intervening intron. Using a series of deletion mutants, we identified an 18-nucleotide purine-rich splicing enhancer in exon 5 that increases the splicing efficiency of the upstream intron from 6 to 35%. We show that the serine-arginine protein splicing factor-2/alternative splicing factor specifically promotes splicing in cultured cells and in vitro and is recruited to the spliceosome in an enhancer-specific manner. Our findings are consistent with a role for splicing factor-2/alternative splicing factor in the regulation of splicing of IGF-I alternative exon 5 via a purine-rich exonic splicing enhancer.