ABNORMAL BONE-GROWTH AND SELECTIVE TRANSLATIONAL REGULATION IN BASIC FIBROBLAST GROWTH-FACTOR (FGF-2) TRANSGENIC MICE

Basic fibroblast growth factor (FGF-2) is a pleiotropic growth factor detected in many different cells and tissues. Normally synthesized at low levels, FGF-2 is elevated in various pathologies, most notably in cancer and injury repair. To investigate the effects of elevated FGF-2 , the human full-length cDNA was expressed in transgenic mice under co ntrol of a phosphoglycerate kinase promoter. Overexpression of FGF-2 c aused a variety of skeletal malformations including shortening and fla ttening of long bones and moderate macrocephaly. Comparison by Western blot of FGF-2 transgenic mice to nontransgenic littermates showed exp ression of human FGF-2 protein in all major organs and tissues examine d including brain, heart, lung, liver, kidney, spleen, and skeletal mu scle; however, different molar ratios of FGF-2 protein isoforms were o bserved between different organs and tissues. Some tissues preferentia lly synthesize larger isoforms of FGF-2 while other tissues produce pr edominantly smaller 18-kDa FGF-2. Translation of the high molecular we ight isoforms initiates from unconventional CUG codons and translation of the 18-kDa isoform initiates from an AUG codon in the FGF-2 mRNA. Thus the Western blot data from the FGF-2 transgenic mice suggest that tissue-specific expression of FGF-2 isoforms is regulated translation ally.