TRANSLATIONAL ENHANCEMENT OF FGF-2 BY EIF-4 FACTORS, AND ALTERNATE UTILIZATION OF CUG AND AUG CODONS FOR TRANSLATION INITIATION

The FGF-2 mRNA of most mammals contains a long and inhibitory 5' UTR i n addition to at least two CUG codons upstream and in frame with the A UG start codon. These CUGs are used for translation initiation to gene rate several polypeptides, Cells overexpressing the translation initia tion factor 4E produce and secrete large amounts of FGF-2, and particu larly the largest, CUG1-initiated form. Overexpression of FGF-2 ia due to a translational enhancement of its mRNA, as indicated by its assoc iation with large polyribosomes in contrast to control cells, where it partitions mostly in fractions lighter than 80 S or small polyribosom es. Breast carcinomas expressing elevated eIF-4E also exhibit the larg e FGF-2 isoforms, which could play an important role in tumor angiogen esis. Translation of in vitro transcribed rat FGF-2 in reticulocyte ly sates resulted in synthesis of four polypeptides, of similar size to t hose observed in vivo. Addition of purified eIF-4E preferentially incr eased translation of CUG1- and AUG-initiated isoforms. Since the diffe rent isoforms of FGF-2 may have different roles and intracellular dist ribution, the effects of the eIF-4 factors on FGF-2 expression could b e important for the control of cell proliferation and differentiation.