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 maintenance 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 following serum deprivation. Apoptosis induced by serum withdrawal is lower in aged RPE cells because of higher endogenous acidic fibroblast growth factor (FGF1) synthesis and secretion. These experiments examined several aspects of FGF signaling and the contribution of endogenous FGF1 to activation of the extracellular signal-regulated kinase 2 (ERK2). In aged RPE cells, FGFR1 was rapidly activated, and its autophosphorylation followed the kinetics of endogenous FGF1 secretion, before the onset of apoptosis. ERK2 phosphorylation, activity, and de novo synthesis increased at the same time. In marked contrast, no de novo JNK1 synthesis was observed. MEK1 inhibition resulted in lower levels of ERK2 activation 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-increasing effect of FGF1 in aged RPE cells is because of an autocrine/paracrine loop in which the ERK2 cascade plays a pivotal role.
Développement, Vieillissement et Pathologie de la Rétine, INSERM U. 450, Affiliée CNRS, Association Claude Bernard-29, rue Wilhem, 75016, Paris, France.
X
X
Guillonneau
M
M
Bryckaert
C
C
Launay-Longo
Y
Y
Courtois
F
F
Mascarelli
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D005346:Fibroblast Growth Factors / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000201:enzymology*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation
D016895:Culture Media, Serum-Free; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D019950:Mitogen-Activated Protein Kinase 1