Involvement of protein kinase A in fibroblast growth factor-2-activated transcription

Polypeptide growth factors activate common signal transduction pathways, ye t they can induce transcription of different target genes. The mechanisms t hat control this specificity are not completely understood. Recently, we ha ve described a fibroblast growth factor (FGF)-inducible response element, F IRE, on the syndecan-1 gene. In NIH 3T3 cells, the FiRE is activated by FGF -2 but not by several other growth factors, such as platelet-derived growth factor or epidermal growth factor, suggesting that FGF-2 activates signali ng pathways that diverge from pathways activated by other growth factors. I n this paper, we report that the activation of FIRE by FGF-2 requires prote in kinase A (PKA) in NIH 3T3 cells. The PKA-specific inhibitor H-89 (N-[2-( p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide) blocked the FGF-2-in duced activation of FIRE, the transcription of the syndecan-1 gene, and cel l proliferation. Also, expression of a dominant-negative form of PKA inhibi ted the FC F-2-induced FIRE activation and the transcription of the syndeca n-1 gene. The binding of activator protein-1 transcription-factor complexes , required for the activation of FIRE, was blocked by inhibition of PKA act ivity before FGF-2 treatment. In accordance with the growth factor specific ity of FiRE, the activity of PKA was stimulated by FGF-2 but not by platele t-derived growth factor or epidermal growth factor. Furthermore, a portion of the PKA catalytic subunit pool was translocated to the nucleus by FGF-2. Noticeably, the total cellular cAMP concentration was not affected by FGF- 2 stimulus. We propose that the FGF-2-selective transcriptional activation through FIRE is caused by the ability of FGF-2 to control PKA activity.