ENDOGENOUS FGF1-INDUCED ACTIVATION AND SYNTHESIS OF EXTRACELLULAR SIGNAL-REGULATED KINASE-2 REDUCE CELL APOPTOSIS IN RETINAL-PIGMENTED EPITHELIAL-CELLS

Retinal-pigmented epithelial (RPE) cell survival is critical to the ma intenance of the function of the neural retinal and in the development of various retina degenerations. We investigated molecular mechanisms involved in this function by assessing apoptosis in RPE cells followi ng serum deprivation. Apoptosis induced by serum withdrawal is lower i n aged RPE cells because of higher endogenous acidic fibroblast growth factor (FGF1) synthesis and secretion. These experiments examined sev eral aspects of FGF signaling and the contribution of endogenous FGF1 to activation of the extracellular signal-regulated kinase 2 (ERK2). I n aged RPE cells, FGFR1 was rapidly activated, and its autophosphoryla tion followed the kinetics of endogenous FGF1 secretion, before the on set of apoptosis. ERK2 phosphorylation, activity, and de novo synthesi s increased at the same time. In marked contrast, no de novo JNK1 synt hesis was observed. MEK1 inhibition resulted in lower levels of ERK2 a ctivation and synthesis and higher levels of apoptosis. Treatment with neutralizing anti-FGF1 or blocking anti-FGFR1 antibodies mimics these effects. Thus, this study strongly suggests that the survival-increas ing effect of FGF1 in aged RPE cells is because of an autocrine/paracr ine loop in which the ERK2 cascade plays a pivotal role.