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Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

Oncogene volume 25, pages 4076–4085 (2006)Cite this article

Abstract

Astrocyte death has been implicated in several neuropathological diseases, but the identification of molecules susceptible of promoting astrocyte survival has been elusive. We investigated whether transforming growth factor alpha (TGFα), an erbB1/EGFR ligand, which promotes glioma progression and affects astrocyte metabolism at embryonic and adult stages, regulates astrocyte survival. Primary serum-free astrocyte cultures from post-natal mouse and fetal human cortices were used. Transforming growth factor alpha protected both species of astrocytes from staurosporine-induced apoptosis. In serum-free medium, mouse astrocytes did not survive beyond 2 months while TGFα-treated astrocytes survived up to 12 months. Transforming growth factor alpha also promoted long-term survival of human astrocytes. We additionally extended TGFα proliferative effects to human astrocytes. After 3 days of permanent application, TGFα induced a major downregulation of both erbB1 and erbB2. This downregulation did not impair the functional activation of the receptors, as ascertained by their tyrosine phosphorylation and the continuous stimulation of both ERK/MAPK and PI3K/Akt pathways up to 7 days, the longest time examined. The full cellular effects of TGFα required activation of both transduction pathways. Enhanced proliferation and survival thus define TGFα as a gliatrophin for mammalian astrocytes. These results demonstrate that in normal, non-transformed astrocytes, sustained and functional erbBs activation is achieved without bypassing ligand-induced receptors downregulation.

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References

  • Bakhiet M, Tjernlund A, Mousa A, Gad A, Stromblad S, Kuziel WA et al. (2001). Nat Cell Biol 3: 150–157.

  • Barna BP, Mattera R, Jacobs BS, Drazba J, Estes ME, Prayson RA et al. (2001). Cell Immunol 208: 18–24.

  • Beck G, Fainzilber M . (2002). Neuron 33: 673–675.

  • Bergmann A, Tugentman M, Shilo BZ, Steller H . (2002). Dev Cell 2: 159–170.

  • Boillee S, Cadusseau J, Coulpier M, Grannec G, Junier MP . (2001). J Neurosci 21: 7079–7088.

  • Busse D, Doughty RS, Ramsey TT, Russell WE, Price JO, Flanagan WM et al. (2000). J Biol Chem 275: 6987–6995.

  • Chakravarti A, Chakladar A, Delaney MA, Latham DE, Loeffler JS . (2002). Cancer Res 62: 4307–4315.

  • Ciardiello F, Tortora G . (2003). Eur J Cancer 39: 1348–1354.

  • Di Iorio P, Ballerini P, Traversa U, Nicoletti F, D'Alimonte I, Kleywegt S et al. (2004). Glia 46: 356–368.

  • Duronio V, Scheid MP, Ettinger S . (1998). Cell Signal 10: 233–239.

  • Elenius K, Paul S, Allison G, Sun J, Klagsbrun M . (1997). EMBO J 16: 1268–1278.

  • Erlich S, Shohami E, Pinkas-Kramarski R . (2000). Mol Cell Neurosci 16: 597–608.

  • Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS et al. (1998). J Biol Chem 273: 18623–18632.

  • Fernandez PA, Tang DG, Cheng L, Prochiantz A, Mudge AW, Raff MC . (2000). Neuron 28: 81–90.

  • Francis A, Raabe TD, Wen D, DeVries GH . (1999). J Neurosci Res 57: 487–494.

  • Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C . (2003). Oncogene 22: 8983–8998.

  • Gerecke KM, Wyss JM, Karavanova I, Buonanno A, Carroll SL . (2001). J Comp Neurol 433: 86–100.

  • Giffard RG, Swanson RA . (2005). Glia 50: 299–306.

  • Hanson Jr MG, Shen S, Wiemelt AP, McMorris FA, Barres BA . (1998). J Neurosci 18: 7361–7371.

  • Hertz L, Zielke HR . (2004). Trends Neurosci 27: 735–743.

  • Hidalgo A, Kinrade EF, Georgiou M . (2001). Dev Cell 1: 679–690.

  • Junier MP . (2000). Prog Neurobiol 62: 443–473.

  • Justicia C, Planas AM . (1999). J Cereb Blood Flow Metab 19: 128–132.

  • Justman QA, Clinton GM . (2002). J Biol Chem 277: 20618–20624.

  • Kari C, Chan TO, Rocha de Quadros M, Rodeck U . (2003). Cancer Res 63: 1–5.

  • Kerr DA, Llado J, Shamblott MJ, Maragakis NJ, Irani DN, Crawford TO et al. (2003). J Neurosci 23: 5131–5140.

  • Klapper LN, Glathe S, Vaisman N, Hynes NE, Andrews GC, Sela M et al. (1999). Proc Natl Acad Sci USA 96: 4995–5000.

  • Kornblum HI, Hussain R, Wiesen J, Miettinen P, Zurcher SD, Chow K et al. (1998). J Neurosci Res 53: 697–717.

  • Kornblum HI, Zurcher SD, Werb Z, Derynck R, Seroogy KB . (1999). Eur J Neurosci 11: 3236–3246.

  • Krueger BK, Burne JF, Raff MC . (1995). J Neurosci 15: 3366–3374.

  • Lee DC, Fenton SE, Berkowitz EA, Hissong MA . (1995). Pharmacol Rev 47: 51–85.

  • Lemke G . (2001). Annu Rev Neurosci 24: 87–105.

  • Leutz A, Schachner M . (1981). Cell Tissue Res 220: 393–404.

  • Levison SW, Jiang FJ, Stoltzfus OK, Ducceschi MH . (2000). Glia 32: 328–337.

  • Malumbres M, Pellicer A . (1998). Front Biosci 3: d887–d912.

  • Matsui Y, Halter SA, Holt JT, Hogan BL, Coffey RJ . (1990). Cell 61: 1147–1155.

  • Moghal N, Sternberg PW . (1999). Curr Opin Cell Biol 11: 190–196.

  • Morrison RS, Kornblum HI, Leslie FM, Bradshaw RA . (1987). Science 238: 72–75.

  • Peschard P, Park M . (2003). Cancer Cell 3: 519–523.

  • Pinkas-Kramarski R, Eilam R, Alroy I, Levkowitz G, Lonai P, Yarden Y . (1997). Oncogene 15: 2803–2815.

  • Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A . (2001). Endocr Relat Cancer 8: 11–31.

  • Prevot V, Lomniczi A, Corfas G, Ojeda SR . (2005). Endocrinology 146: 1465–1472.

  • Prevot V, Rio C, Cho GJ, Lomniczi A, Heger S, Neville CM et al. (2003). J Neurosci 23: 230–239.

  • Rabchevsky AG, Weinitz JM, Coulpier M, Fages C, Tinel M, Junier MP . (1998). J Neurosci 18: 10541–10552.

  • Riese II DJ, Stern DF . (1998). BioEssays 20: 41–48.

  • Rodriguez D, Gauthier F, Bertini E, Bugiani M, Brenner M, N'guyen S et al. (2001). Am J Hum Genet 69: 1134–1140.

  • Ruegg UT, Burgess GM . (1989). Trends Pharmacol Sci 10: 218–220.

  • Saas P, Walker PR, Quiquerez AL, Chalmers DE, Arrighi JF, Lienard A et al. (2002). NeuroReport 13: 1921–1924.

  • Schlessinger J . (2004). Science 306: 1506–1507.

  • Schreiner B, Baur DM, Fingerle AA, Zechner U, Greten FR, Adler G et al. (2003a). Genes Chromosomes Cancer 38: 240–248.

  • Schreiner B, Greten FR, Baur DM, Fingerle AA, Zechner U, Bohm C et al. (2003b). Oncogene 22: 6802–6809.

  • Sibilia M, Steinbach JP, Stingl L, Aguzzi A, Wagner EF . (1998). EMBO J 17: 719–731.

  • Soriano E, Del Rio JA, Auladell C . (1993). J Histochem Cytochem 41: 819–827.

  • Sweeney C, Carraway III KL . (2004). Br J Cancer 90: 289–293.

  • Takuma K, Baba A, Matsuda T . (2004). Prog Neurobiol 72: 111–127.

  • Tang P, Steck PA, Yung WK . (1997). J Neurooncol 35: 303–314.

  • Thomas LB, Gates DJ, Richfield EK, O'Brien TF, Schweitzer JB, Steindler DA . (1995). Exp Neurol 133: 265–272.

  • Thompson KA, McArthur JC, Wesselingh SL . (2001). Ann Neurol 49: 745–752.

  • Tokita Y, Keino H, Matsui F, Aono S, Ishiguro H, Higashiyama S et al. (2001). J Neurosci 21: 1257–1264.

  • Waterman H, Sabanai I, Geiger B, Yarden Y . (1998). J Biol Chem 273: 13819–13827.

  • Wechsler-Reya R, Scott MP . (2001). Annu Rev Neurosci 24: 385–428.

  • Weickert CS, Blum M . (1995). Dev Brain Res 86: 203–216.

  • Wiley HS . (2003). Exp Cell Res 284: 78–88.

  • Wu CJ, Chen Z, Ullrich A, Greene MI, O'Rourke DM . (2000). Oncogene 19: 3999–4010.

  • Xian CJ, Zhou XF . (1999). Mol Neurobiol 20: 157–183.

  • Yaish P, Gazit A, Gilon C, Levitzki A . (1988). Science 242: 933–935.

  • Yarden Y, Sliwkowski MX . (2001). Nat Rev Mol Cell Biol 2: 127–137.

  • Yokoyama M, Black IB, Dreyfus CF . (1993). Exp Neurol 124: 377–380.

  • Zelenaia O, Schlag BD, Gochenauer GE, Ganel R, Song W, Beesley JS et al. (2000). Mol Pharmacol 57: 667–678.

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Acknowledgements

We are grateful to Professor Jacques Glowinski for his constant support. We thank Amelia Dias-Morais and Yvette Thorens for their expert technical help, and Annette Koulakoff for generously sharing her knowledge of cell cultures. This research was supported by the Association pour la Recherche contre le Cancer (ARC, grant# 3500 to HC, and study fellowship to AS), the Fondation pour la Recherche Medicale (FRM, grant to VP), the Académie Nationale de Médecine (study fellowhip to FR-M), the Centre Hospitalier Universitaire de Lille and the Région Nord Pas de Calais (study fellowships to CA).

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Authors and Affiliations

  1. Inserm U752, Paris, F-75013, France

    A Sharif, F Renault-Mihara, J-M Studler, B Canton, H Chneiweiss & M-P Junier

  2. University of Paris 5, Paris, F-75013, France

    A Sharif, F Renault-Mihara, J-M Studler, B Canton, H Chneiweiss & M-P Junier

  3. Inserm U114, Paris, F-75005, France

    A Sharif, F Renault-Mihara, J-M Studler, B Canton, H Chneiweiss & M-P Junier

  4. Inserm U816, Lille, F-59000, France

    V Prévot & C Allet

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Sharif, A., Prévot, V., Renault-Mihara, F. et al. Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes. Oncogene 25, 4076–4085 (2006). https://doi.org/10.1038/sj.onc.1209443

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