Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Regulation of proliferation-survival decisions is controlled by FGF1 secretion in retinal pigmented epithelial cells

Oncogene volume 19, pages 4917–4929 (2000)Cite this article

Abstract

Fibroblast growth factor 1 (FGF1) induces proliferation and differentiation in a wide variety of cells of mesodermal and neuroectodermal origin. FGF1 has no ‘classical’ signal sequence to direct its secretion, and there has been considerable debate concerning FGF1 secretion and its role in the biological activities of FGF1. We investigated the effects of FGF1 secretion and the signalling induced by signal peptide (SP)-containing FGF1 and SP-less FGF1, on the proliferation and the apoptosis in retinal pigmented epithelial (RPE) cells. Primary RPE cell cultures were transfected with FGF1 (FGF1 cells) and SP-FGF1 (SP-FGF1 cells) cDNAs. SP-FGF1 cells secreted large amount of FGF1 and actively proliferated, whereas FGF1 and control cells did not. Secreted FGF1 induced short-term activation of both FGFR1 and ERK2, which were required for cell proliferation. In contrast, SP-FGF1 cells stopped secreting FGF1 and died rapidly, if cultured in the absence of serum. Surprisingly, FGF1 cells, but not control cells, secreted FGF1 and were resistant to apoptosis induced by serum depletion. Secreted FGF1 induced long-term activation of FGFR1 and ERK2, which was necessary to induce a constant and high level of Bcl-x production, and to induce cell survival in FGF1 cells. Downregulation of ERK2 and Bcl-x increased apoptosis. Thus, the proliferation and survival activities of FGF1 depend on the secretion of FGF1 which is determined by the cell culture conditions. Cell proliferation was SP-dependent, whereas cell survival was not. The signal peptide controls the level and duration, ‘whispering or shouting’, of ERK2 activation cells which determines FGF1 biological function and may have important implications for anti-degenerative and anti-proliferative treatments.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Ananyeva N, Tjurmin A, Berliner J, Chisolm G, Liau G, Winkles J and Haudenschild C. . 1997 Arter. Thromb. Vasc. Biol. 17:: 445–453.

  • Amarente-Mendes G, McGahon A, Nishioka W, Afar D, Witte O and Green D. . 1998 Oncogene 16:: 1383–1390.

  • Basilico C and Moscatelli D. . 1992 Adv. Cancer Res. 59:: 115–165.

  • Baudouin C, Fredj-Reygrobeller D, Brignole F, Negre F, Lapalus P and Gastaud P. . 1993 Ophthalmic Res. 25: 52–59.

  • Blam SB, Mitchell R, Tischer E, Rubin JS, Silva M, Silver S, Fiddes JC, Abraham JA and Aaronson SA. . 1988 Oncogene 3:: 129–136.

  • Boise L, Gonzales-Garcia M, Postela C, Ding L, Lindsten T, Turka L, Mao X, Nunez G and Thompson C. . 1993 Cell 74: 597–608.

  • Bonnet H, Filhol O, Truchet I, Brethenou P, Cochet C, Amalric F and Bouche G. . 1996 J. Biol. Chem. 271:: 24781–24787.

  • Bouche G, Gas N, Prats H, Baldin V, Tauber JP, Teissie J and Amalric F. . 1987 Proc. Natl. Acad. Sci. USA 84:: 6770–6774.

  • Bradshaw RA, Altin JG, Cavanaugh KP, Eveleth DD, Kornblum HI, Leslie FM and Raffioni S. . 1990 Prog. Brain Res. 86:: 157–167.

  • Burgess WH and Maciag T. . 1989 Annu. Rev. Biochem. 58: 575–606.

  • Bryckaert M, Guillonneau X, Hecquet C, Courtois Y and Mascarelli F. . 1999 Oncogene 18: 7584–7593.

  • Cao Y and Pettersson R. . 1993 Growth Factors 8:: 277–290.

  • Carter S, Auer K, Reardon D, Birrer M, Fisher P, Valerie K, Schmidt-Ullrich R, Mikkelsen R and Dent P. . 1998 Oncogene 16:: 2787–2796.

  • Chen J, Flannery JG, LaVail M and Steinbert RH. . 1996 Proc. Natl. Acad. Sci. USA 93:: 7042–7047.

  • Chesnut JD, Baytan AR, Russel M, Chang MP, Bernard A, Maxwell IH and Hoeffler JP. . 1996 J. Immunol. Methods 193: 17–27.

  • Clarenc J, Lebleu B and Leonetti J. . 1993 J. Biol. Chem. 268:: 5600–5604.

  • Chen J, Flannery J, LaVail M, Steinberg R, Xu J and Simon M. . 1996 Proc. Natl. Acad. Sci. USA 93:: 7042–7047.

  • Chomczynski P and Sacchi N. . 1987 Anal. Biochem. 162:: 156–159.

  • Dennis PA and Rifkin DB. . 1990 J. Cell Physiol. 144:: 84–98.

  • Désiré L, Head M, Fayen N, Courtois Y and Jeanny JC. . 1998 Dev. Dynamics 212:: 63–74.

  • Enzmann V, Faude F, Kohen L and Wiedmann P. . 1998 Ophthalmic Res. 30: 189–194.

  • Faktorovich E, Steinberg R, Yasumara D and LaVail M. . 1990 Nature 347:: 83–86.

  • Fenig E, Livnat T, Sharkon-Polak S, Wasserman L, Beery E, Lilling G, Yaholom J, Wieder R and Nordenberg J. . 1999 J. Cancer Res. Clin. Oncol. 125:: 556–562.

  • Fennwald S and Rando R. . 1995 J. Biol. Chem. 270:: 21718–21721.

  • Forough R, Xi Z, MacPhee M, Friedman S, Engleka KA, Sayers T, Wiltrout RH and Maciag T. . 1993 J. Biol. Chem. 268:: 2960–2968.

  • Guillonneau X, Bryckaert MC, Launay-Longo C, Courtois Y and Mascarelli F. . 1998b J. Biol. Chem. 273:: 22367–22373.

  • Guillonneau X, Regnier-Ricard F, Dupuis C, Courtois Y and Mascarelli F. . 1997 Exp. Cell Res. 233:: 198–206.

  • Guillonneau X, Regnier-Ricard F, Dupuis C, Courtois Y and Mascarelli F. . 1998a Growth Factors 15:: 95–112.

  • Guillonneau X, Regnier-Ricard F, Jeanny JC, Thomasseau S, Courtois Y and Mascarelli F. . 2000 Dev. Dyn. 217:: 24–36.

  • Guillonneaux X, Tassin J, Berrou E, Bryckaert M and Courtois Y. . 1996 J. Cell. Physiol. 166: 170–187.

  • Guvakova M, Yakubov L, Vlodavsky I, Tonkinson J and Stein C. . 1995 J. Biol. Chem. 270:: 2620–2627.

  • Hackett SF, Shoenfield CL, Freunf J, Gottesch JD, Bhargrave S and Campochiaro PA. . 1997 Exp. Eye Res. 64:: 865–873.

  • Her JH, Wu J, Rall TB, Sturgill TW and Weber MJ. . 1991 Nucleic Acids Res. 19:: 37–43.

  • Hjelmeland LM and Harvey AK. . 1988 Birth Defects Orig., Artic. Ser. 24:: 87–102.

  • Hinton D, He S and Lopez F. . 1998 Arch. Ophthalmol. 116:: 203–209.

  • Imamura T, Oka S, Tanahashi T and Okita Y. . 1994 Exp. Cell Res. 215: 363–372.

  • Jackson A, Friedman S, Zhan X, Engleka KA, Forough R and Maciag T. . 1992 Proc. Natl. Acad. Sci. USA 89:: 10691–10695.

  • Jaye M, Lyall RM, Mudd R, Schlessinger J and Sarver N. . 1988 EMBO J. 7:: 963–969.

  • Jouanneau J, Gavrilovic J, Caruelle D, Jaye M, Moens G, Caruelle JP and Thiery JP. . 1991 Proc. Natl. Acad. Sci. USA 88:: 2893–2897.

  • Jouanneau J, Moens G, Montesan R and Thiery JP. . 1994 Growth Factors 12:: 37–47.

  • Jouanneau J, Plouet J, Moens G and Thiery JP. . 1997 Oncogene 14:: 671–676.

  • Karsan A, Yee E, Zhou P, Poirier GG, Craig R and Harlan JM. . 1997 Am. J. Pathol. 151:: 1775–1785.

  • Klingenberg O, Wiedlocha A and Oslnes S. . 1999 J. Biol. Chem. 274:: 18081–18086.

  • König A, Menzel T, Lynen S, Wrazel L, Rosén A, Al-Katib A, Raveche E and Gabrilove JL. . 1997 Leukemia 11:: 258–265.

  • Levin L, Sclamp C, Spieldoch R, Gesvain K and Nickells R. . 1997 Invest. Ophthalmol. Vis. Sci. 38:: 2545–2553.

  • Lewis GP, Erickson PA, Guerin CJ, Anderson DH and Fisher SK. . 1992 J. Neurosci. 12:: 3968–3972.

  • Lezoualc'h F, Seugnet I, Monnier AL, Ghysdael J, Behr J and Demeinex B. . 1995 J. Biol. Chem. 270:: 12100–12108.

  • Lin YZ, Yao SY and Hawiger J. . 1996 J. Biol. Chem. 271:: 5305–5308.

  • Malecaze F, Mascarelli F, Bugra K, Fuhrmann G, Courtois Y and Hicks D. . 1993 J. Cell Physiol. 8:: 631–642.

  • Maloof P, Wang Q, Stein D, Denny TN, Yahalom J, Fenig E and Wieder R. . 1999 Breast Cancer Res. Treat. 56:: 153–167.

  • Mason I. . 1994 Curr. Biol. 4: 1158–1161.

  • Mascarelli F, Raulais D and Courtois Y. . 1989 EMBO J. 8:: 2265–2273.

  • Mishima K, Yamada E, Masui K, Shimokawara T, Sugimura M and Ichijima K. . 1998 Mod. Pathol. 11:: 886–891.

  • Navarro P, Valverde A, Benito M and Lorenzo M. . 1998 Exp. Cell Res. 243:: 213–221.

  • Raguenez G, Desiré L, Lantrua V and Courtois Y. . 1999 Biochem. Biophys. Res. Commun. 258:: 745–751.

  • Rapraeger AC, Krufka A and Olwin BB. . 1991 Science 252:: 1705–1708.

  • Ren G, Fuse N, Abe T and Tamai M. . 2000 Jpn. J. Ophthalmol. 44: 308–311.

  • Renaud F, Desset S, Oliver L, Gimenez-Gallego G, Van Obberghen E, Courtois Y and Laurent M. . 1996 J. Biol. Chem. 271:: 2801–2811.

  • Rifkin D and Moscatelli D. . 1989 J. Cell. Biol. 109:: 1–6.

  • Roghani M, Mansukkhani A, Dell'Era P, Bellosta P, Basilico C, Rifkin DB and Moscatelli D. . 1994 J. Biol. Chem. 269:: 3976–3984.

  • Sale EM, Atkinson PGP and Sale GJ. . 1995 EMBO J. 14:: 674–684.

  • Sato Y and Rifkin DB. . 1988 J. Cell. Biol. 107:: 1129–1205.

  • Shin JT, Opalenik SR, Wehby JN, Mahesh VK, Jackson A, Tarantini F, Maciag T and Thompson JA. . 1996 Biochim. Biophys. Acta. 1312:: 27–38.

  • Sivaraman VS, Wang H, Nuovo GJ and Malbon CC. . 1997 J. Clin. Invest. 99:: 1478–1483.

  • Spear N, Estevez AG, Johnson GV, Bredesen DE, Thompson JA and Beckman JS. . 1998 Arch. Biochem. Biophys. 356:: 41–45.

  • Vlodavski I, Arias Y, Atzman R and Fuks Z. . 1982 Exp. Cell. Res. 140:: 149–159.

  • Wang Q, Maloof P, Wang H, Faenig E, Stein D, Nichols G, Denny TN, Yahalom J and Wieder R. . 1998 Exp. Cell. Res. 238:: 177–187.

  • Wiedlocha A, Falnes PO, Madshus IH, Sandwvig K and Oslnes S. . 1994 Cell 76:: 1039–1051.

  • Wiedlocha A, Falnes PO, Rapak A, Munoz R, Klingenberg O and Oslnes S. . 1996 Mol. Cell Biol. 16:: 270–280.

  • Yayon A and Klagsbrun M. . 1990 Proc. Natl. Acad. Sci. USA 87:: 5346–5350.

  • Yazlovitskaya EM, Pelling JC and Person DI. . 1999 Mol. Carcinog. 25:: 14–20.

  • Zhan X, Hu X, Friedman S and Maciag T. . 1992 Biochim. Biophys. Res. Commun. 188:: 982–991.

  • Zhan X, Hu X, Friesel R and Maciag T. . 1993 J. Biol. Chem. 268:: 9611–9620.

Download references

Acknowledgements

The authors wish to thank C Tonnerre-Doncarli for excellent technical and H Coet for meticulous photographic work. We thank Dr JC Jeanny and Dr J Jouanneau for helpful discussions and critical reading of the manuscript. This work was supported by the Association pour la Recherche contre le Cancer (Contract numbers 1369 and 9697, F Mascarelli), the Université René Descartes, Faculté de Médecine Paris-Ouest (F Mascatelli) and the Ligue Nationale contre le Cancer (Comité de Paris, M Bryckaert).

Author information

Authors and Affiliations

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

    Marijke Bryckaert

  2. Développement, vieillissement et pathologie de la rétine, INSERM U. 450, affiliée CNRS, Association Claude,

    Xavier Guillonneau, Christiane Hecquet, Paolo Perani, Yves Courtois & Frederic Mascarelli

  3. Bernard - 29, rue Wilhem, Paris, 75016, France

    Xavier Guillonneau, Christiane Hecquet, Paolo Perani, Yves Courtois & Frederic Mascarelli

Authors
  1. Marijke Bryckaert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xavier Guillonneau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christiane Hecquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paolo Perani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yves Courtois
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frederic Mascarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bryckaert, M., Guillonneau, X., Hecquet, C. et al. Regulation of proliferation-survival decisions is controlled by FGF1 secretion in retinal pigmented epithelial cells. Oncogene 19, 4917–4929 (2000). https://doi.org/10.1038/sj.onc.1203872

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203872

Keywords

This article is cited by

Search

Advanced search

Quick links