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
E. Arnaud et al., 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, MOL CELL B, 19(1), 1999, pp. 505-514
Four isoforms of human fibroblast growth factor 2 (FGF-2) result from alter
native initiations of translation at three CUG start codons and one AUG sta
rt 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 codo
n 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 translatio
n and COS-7 cell transfection using bicistronic RNAs demonstrated that the
34-kDa FGF-2 was exclusively expressed in a cap-dependent manner. This cont
rasted 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 ORES). Stri
kingly, 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 I
RES-driven mechanisms, the balance between these two mechanisms modulating
the ratio of the different FGF-2 isoforms. The function of the new FGF-2 wa
s also investigated. We found that the 34-kDa FGF-2, in contrast to the oth
er 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 o
f human immunodeficiency virus type 1 Rev protein. These data suggest that
the function of the 34-kDa FGF-2 is mediated by nuclear targets.