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  • Original Paper
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Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Oncogene volume 18, pages 7584–7593 (1999)Cite this article

Abstract

Retinal pigmented epithelial (RPE) cells are of central importance in the maintenance of neural retinal function. Changes in the RPE cells associated with repair activities have been described as metaplasia, while RPE cell apoptosis is responsible for the development of a variety of retinal degenerations. We investigated the regulation of the anti-apoptotic properties of the fibroblast growth factors (FGF) 2 in serum-free cultures of RPE cells. In the absence of serum, confluent stationary RPE cells died by apoptosis via a caspase 3-dependent pathway. The addition of FGF2 greatly reduced apoptosis over a 7-day culture period. We demonstrated the involvement of an autocrine loop involving endogenous FGF1 in the mechanisms that govern FGF2-induced resistance to apoptosis by showing: (1) higher levels of apoptosis in cells treated with antisense FGF1 oligonucleotide or after neutralization of excreted FGF1; (2) the long-term activation of FGFR1 and of ERK2, (3) the inhibition of FGFR1 and ERK2 activation and an increase in apoptosis if excreted FGF1 was neutralized. FGF2 also increased the de novo synthesis and the production of Bcl-xl before the onset of apoptosis. Both inhibition of ERK2 activation, which decreased Bcl-xl synthesis, and downregulation of Bcl-x by antisense oligonucleotide treatment inhibited the survival-promoting activity of FGF2. Thus, FGF2-induced cell survival is a progressive adaptive phenomenon involving ERK2 activation by excreted FGF1 and ERK2-dependent Bcl-x production.

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Acknowledgements

The authors wish to thank Dr JC Jeanny and Dr L Désiré for helpful suggestions. The excellent technical assistance of F Regnier-Ricard is gratefully acknowledged. This work was supported by the Association pour la Recherche sur le Cancer (contract numbers 1369 and 9697, F Mascarelli), the Ligue Nationale contre le Cancer (Comité de Paris, M Bryckaer), the Ministère de la Recherche et de l'Enseignement Supérieur (X Guillonneau) and the Universite René Descartes, Faculté de Médecine Paris-Ouest (F Mascarelli).

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  1. Développement, vieillissement et pathologie de la rétine, INSERM U. 450, affiliée CNRS, Association Claude Bernard - 29, rue Wilhem, 75016, Paris, France

    Xavier Guillonneau, Christiane Hecquet, Yves Courtois & Frédéric Mascarelli

  2. INSERM U. 348, IFR Circulation, 75010, Paris, France

    Marijke Bryckaert

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Bryckaert, M., Guillonneau, X., Hecquet, C. et al. Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2. Oncogene 18, 7584–7593 (1999). https://doi.org/10.1038/sj.onc.1203200

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