Abstract
We created an FGF1:FGF2 chimera (FGFC) previously and showed that it was useful in clinical applications for treatment of radiation injuries because of its high radioprotective effects. FGFC had the same receptor specificity as FGF1, but not FGF2, despite FGF2 being a component of FGFC. Therefore, FGFC may be functionally consistent with FGF1. This study evaluated the contribution of the structural stability of FGF1 protein to the radioprotective activity of FGFC through analysis of FGFC and FGF1 stable mutant (Q40P/S47I/H93G; Zakrzewska et al., J Mol Biol, 2005). FGF1, FGFC and Q40P/S47I/H93G were administered intraperitoneally to BALB/c mice 24 h before or after total body irradiation (TBI). The surviving numbers of crypts per circumference were determined 3.5 days after TBI. When each FGF was administered 24 h before irradiation, FGFC and Q40P/S47I/H93G were more effective in promoting crypt survival than FGF1. In addition, they were effective in promoting crypt survival even when it was administered 24 h after TBI at a dose of 10, 11, or 12 Gy, whereas FGF1 was not effective. However, FGFC and Q40P/S47I/H93G increased crypt survival almost equally, although the structural stability of Q40P/S47I/H93G was much higher than that of FGFC. In addition, there was no significant difference between FGFC- and Q40P/S47I/H93G-treatment in promoting BrdU incorporation into crypts, epithelial differentiation, increase of crypt depth and decrease in the number of apoptotic cells. These findings suggest that the structural stabilization of FGF1 results in enhanced radioprotection. This improved stability contributes to the protective effect of FGFC on radiation-induced damage.
