The FGF-2 mRNA of most mammals contains a long and inhibitory 5' UTR in addition to at least two CUG codons upstream and in frame with the AUG start codon. These CUGs are used for translation initiation to generate several polypeptides. Cells overexpressing the translation initiation factor 4E produce and secrete large amounts of FGF-2, and particularly the largest, CUG1-initiated form. Overexpression of FGF-2 is due to a translational enhancement of its mRNA, as indicated by its association with large polyribosomes in contrast to control cells, where it partitions mostly in fractions lighter than 80 S or small polyribosomes. Breast carcinomas expressing elevated eIF-4E also exhibited the large FGF-2 isoforms, which could play an important role in tumor angiogenesis. Translation of in vitro transcribed rat FGF-2 in reticulocyte lysates resulted in synthesis of four polypeptides, of similar size to those observed in vivo. Addition of purified eIF-4F preferentially increased translation of CUG1- and AUG-initiated isoforms. Since the different isoforms of FGF-2 may have different roles and intracellular distribution, the effects of the eIF-4 factors on FGF-2 expression could be important for the control of cell proliferation and differentiation.