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Mol Cell Biol, April 1998, p. 2205-2217, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

An Intronic Sequence Element Mediates Both Activation and Repression of Rat Fibroblast Growth Factor Receptor 2 Pre-mRNA Splicing

Russ P. Carstens,1,2,3 Wallace L. McKeehan,4 and Mariano A. Garcia-Blanco1,3,5,*

Department of Pharmacology and Cancer Biology,1 Division of Nephrology,2 Department of Medicine,3 and Department of Microbiology,5 Duke University Medical Center, Durham, North Carolina, and Department of Biochemistry and Biophysics, Center for Cancer Biology and Nutrition, Albert B. Alkek Institute of Biological Sciences and Technology, Texas A&M University, Houston, Texas4

Received 17 October 1997/Returned for modification 11 December 1997/Accepted 22 January 1998

Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) is an example of highly regulated alternative splicing in which exons IIIb and IIIc are utilized in a mutually exclusive manner in different cell types. The importance of this splicing choice is highlighted by studies which indicate that deregulation of the FGF-R2 splicing is associated with progression of prostate cancer. Loss of expression of a IIIb exon-containing isoform of FGF-R2 [FGF-R2 (IIIb)] accompanies the transition of a well-differentiated, androgen-dependent rat prostate cancer cell line, DT3, to the more aggressive, androgen-independent AT3 cell line. We have used transfection of rat FGF-R2 minigenes into DT3 and AT3 cancer cell lines to study the mechanisms that control alternative splicing of rat FGF-R2. Our results support a model in which an important cis-acting element located in the intron between these alternative exons mediates activation of splicing using the upstream IIIb exon and repression of the downstream IIIc exon in DT3 cells. This element consists of 57 nucleotides (nt) beginning 917 nt downstream of the IIIb exon. Analysis of mutants further demonstrates that an 18-nt "core sequence" within this element is most crucial for its function. Based on our observations, we have termed this sequence element ISAR (for intronic splicing activator and repressor), and we suggest that factors which bind this sequence are required for maintenance of expression of the FGF-R2 (IIIb) isoform.

* Corresponding author. Mailing address: Department of Pharmacology and Cancer Biology, Box 3686, Duke University Medical Center, Durham, NC 27710. Phone: (919) 613-8632. Fax: (919) 613-8646. E-mail: garci001{at}mc.duke.edu.




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