Differential regulation of human fibroblast growth factor 1 transcripts provides a distinct mechanism of cell-specific growth factor expression.

ABSTRACT

Four variants of fibroblast growth factor 1 (FGF-1) mRNA, FGF-1.A, -1.B, -1.C, and -1.D, originate from four discrete promoters of the gene. Each promoter is coupled with its 5'-untranslated exon. These four promoters are separated by as much as 70 kbp in the FGF-1 locus. The present study indicates that expression of these transcripts in different cell types is regulated by distinct mechanisms. FGF-1.C mRNA requires de novo protein synthesis and de novo transcription for expression and processing, and this mRNA increases acutely in response to TGF-beta and serum stimulation. The serum-induced FGF-1.C correlates with a marked increase in protein level. In addition, FGF-1.C mRNA also increases significantly (more than 100-fold) in response to phorbol 12-myristate 13-acetate. FGF-1.D mRNA is uniquely superinduced by serum in the presence of cycloheximide and displays delayed early kinetics, suggesting that this mRNA does not require de novo protein synthesis for expression. In sharp contrast to the FGF-1.C and -1.D mRNAs, FGF-1.B mRNA levels do not increase in response to serum or phorbol 12-myristate 13-acetate and are in fact slightly down-regulated. Furthermore, FGF-1.B mRNA is stable and appears to have a long half-life (> 12 h). Thus, the unique cell-specific regulation of these FGF-1 transcripts and subsequent protein synthesis indicate that each transcript may have a distinct role in development, normal cellular processes, and, upon aberrant regulation, disease. In support of these conclusions, multiple FGF-1 transcripts in normal, fetal, and diseased tissues, containing mixed cell types, were detected. Our results suggest that FGF-1 transcripts FGF-1.C and -1.D arising from promoters 1C and 1D are specific and are potential markers for proliferation of certain cells, whereas transcripts FGF-1.A and -1.B arising from promoters 1A and 1B are specific for maintenance and survival of cells, particularly cardiac and neuronal cells. Together, these data provide evidence for a biological function for multiple promoter usage of a single gene. The discrete mechanisms for expression of the FGF-1 gene further underscore the biological significance of this growth factor.