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Molecular and Cellular Biology, January 1999, p. 505-514, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A New 34-Kilodalton Isoform of Human Fibroblast Growth Factor 2 Is Cap Dependently Synthesized by Using a Non-AUG Start Codon and Behaves as a Survival Factor

Emmanuelle Arnaud, Christian Touriol, Christel Boutonnet,dagger Marie-Claire Gensac, Stéphan Vagner, Hervé Prats, and Anne-Catherine Prats*

INSERM U397, Endocrinologie et Communication Cellulaire, Institut Louis Bugnard, C.H.U. Rangueil, 31403 Toulouse Cedex 04, France

Received 30 July 1998/Returned for modification 28 September 1998/Accepted 15 October 1998

Four isoforms of human fibroblast growth factor 2 (FGF-2) result from alternative initiations of translation at three CUG start codons and one AUG start codon. Here we characterize a new 34-kDa FGF-2 isoform whose expression is initiated at a fifth initiation codon. This 34-kDa FGF-2 was identified in HeLa cells by using an N-terminal directed antibody. Its initiation codon was identified by site-directed mutagenesis as being a CUG codon located at 86 nucleotides (nt) from the FGF-2 mRNA 5' end. Both in vitro translation and COS-7 cell transfection using bicistronic RNAs demonstrated that the 34-kDa FGF-2 was exclusively expressed in a cap-dependent manner. This contrasted with the expression of the other FGF-2 isoforms of 18, 22, 22.5, and 24 kDa, which is controlled by an internal ribosome entry site (IRES). Strikingly, expression of the other FGF-2 isoforms became partly cap dependent in vitro in the presence of the 5,823-nt-long 3' untranslated region of FGF-2 mRNA. Thus, the FGF-2 mRNA can be translated both by cap-dependent and IRES-driven mechanisms, the balance between these two mechanisms modulating the ratio of the different FGF-2 isoforms. The function of the new FGF-2 was also investigated. We found that the 34-kDa FGF-2, in contrast to the other isoforms, permitted NIH 3T3 cell survival in low-serum conditions. A new arginine-rich nuclear localization sequence (NLS) in the N-terminal region of the 34-kDa FGF-2 was characterized and found to be similar to the NLS of human immunodeficiency virus type 1 Rev protein. These data suggest that the function of the 34-kDa FGF-2 is mediated by nuclear targets.

* Corresponding author. Mailing address: INSERM U397, Endocrinologie et Communication Cellulaire, Institut Louis Bugnard, C.H.U. Rangueil, Avenue Jean Poulhès, 31403 Toulouse Cedex 04, France. Phone: 33 (5) 61 32 21 42. Fax: 33 (5) 61 32 21 41. E-mail: pratsac{at}rangueil.inserm.fr.

dagger Present address: Swiss Institute for Experimental Cancer Research, 1066 Epalinges, Switzerland.

Molecular and Cellular Biology, January 1999, p. 505-514, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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