INDUCTION OF MDM2 AND ENHANCEMENT OF CELL-SURVIVAL BY BFGF

Basic fibroblast growth factor (bFGF) can exert mitogenic and viabilit y-promoting effects in a wide range of biological systems. The biochem ical activities mediating the cell survival function of bFGF are large ly unknown. We report here that exposure of fibroblasts to bFGF, which confers upon them increased survival, also causes at the same time an increase in cellular levels of the Mdm2 oncoprotein. Cells constituti vely exposed to a bFGF autocrine loop are more refractory to killing b y cisplatin. This increased chemoresistance coincides with elevated Md m2 and reduced activation of the endogenous p53, resulting in ineffici ent transcriptional activation of the bar gene promoter. Importantly, unlike Mdm2 accumulation in fibroblasts exposed to DNA damage, inducti on of Mdm2 by bFGF does not occur through a p53-mediated pathway. The role of p53 in DNA damage-induced apoptosis and the ability of Mdm2 to block p53-mediated cell death are well established. These findings th erefore suggest that induction of Mdm2 and the subsequent inhibition o f p53 function may contribute, at least partially, to the anti-apoptot ic effects of bFGF and possibly some other survival factors.