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Molecular and Cellular Biology, September 2004, p. 7622-7635, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7622-7635.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Internal Ribosome Entry Site Structural Motifs Conserved among Mammalian Fibroblast Growth Factor 1 Alternatively Spliced mRNAs

Yvan Martineau,1 Christine Le Bec,2 Laurent Monbrun,1 Valérie Allo,2 Ing-Ming Chiu,3 Olivier Danos,2 Hervé Moine,4 Hervé Prats,1 and Anne-Catherine Prats1*

Institut National de la Santé et de la Recherche Médicale U589, Hormones, Facteurs de Croissance et Physiopathologie Vasculaire, Institut Louis Bugnard, IFR31, CHU Rangueil, Toulouse,1 Genethon, CNRS UMR 8115, Evry,2 UPR 9002 CNRS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France,4 Department of Internal Medicine, The Ohio State University, Columbus, Ohio3

Received 8 December 2003/ Returned for modification 5 January 2004/ Accepted 25 May 2004

Fibroblast growth factor 1 (FGF-1) is a powerful angiogenic factor whose gene structure contains four promoters, giving rise to a process of alternative splicing resulting in four mRNAs with alternative 5' untranslated regions (5' UTRs). Here we have identified, by using double luciferase bicistronic vectors, the presence of internal ribosome entry sites (IRESs) in the human FGF-1 5' UTRs, particularly in leaders A and C, with distinct activities in mammalian cells. DNA electrotransfer in mouse muscle revealed that the IRES present in the FGF-1 leader A has a high activity in vivo. We have developed a new regulatable TET OFF bicistronic system, which allowed us to rule out the possibility of any cryptic promoter in the FGF-1 leaders. FGF-1 IRESs A and C, which were mapped in fragments of 118 and 103 nucleotides, respectively, are flexible in regard to the position of the initiation codon, making them interesting from a biotechnological point of view. Furthermore, we show that FGF-1 IRESs A of murine and human origins show similar IRES activity profiles. Enzymatic and chemical probing of the FGF-1 IRES A RNA revealed a structural domain conserved among mammals at both the nucleotide sequence and RNA structure levels. The functional role of this structural motif has been demonstrated by point mutagenesis, including compensatory mutations. These data favor an important role of IRESs in the control of FGF-1 expression and provide a new IRES structural motif that could help IRES prediction in 5' UTR databases.

* Corresponding author. Mailing address: Institut National de la Santé et de la Recherche Médicale U589, Hormones, Facteurs de Croissance et Physiopathologie Vasculaire, Institut Louis Bugnard, IFR31, CHU Rangueil, 31059 Toulouse Cedex 09, France. Phone: 33 (5) 61 32 21 42. Fax: 33 (5) 61 32 21 41. E-mail: pratsac{at}toulouse.inserm.fr.

Molecular and Cellular Biology, September 2004, p. 7622-7635, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7622-7635.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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