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  • Original Paper
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Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function

Oncogene volume 21, pages 2227–2235 (2002)Cite this article

Abstract

Signaling of TGFβ family members such as activin is tightly regulated by soluble binding proteins. Follistatin binds to activin A with high affinity, and prevents activin binding to its own receptors, thereby blocking its signaling. We previously identified FLRG gene from a B-cell leukemia carrying a t(11;19)(q13;p13) translocation. We and others have already shown that FLRG, which is highly homologous to follistatin, may be involved in the regulation of the activin function through its binding to activin. In this study, we found that, like follistatin, FLRG protein inhibited activin A signaling as demonstrated by the use of a transcriptional reporter assay, and blocked the activin A-induced growth inhibition of HepG2 cells. We have recently shown that the TGFβ-induced expression of FLRG occurs at a transcriptional level through the action of Smad proteins. Here we show that activin A increases FLRG and follistatin at both the mRNA and protein levels. We found that Smad proteins are involved in the activin A-induced transcription activation of FLRG and follistatin. Finally we demonstrate that FLRG protein regulates its own activin-induced expression. In conclusion, activin A induces FLRG and follistatin expression. This observation, in conjunction with the antagonistic effect of FLRG and follistatin on activin signaling, indicates that these two proteins participate in a negative feedback loop which regulates the activin function.

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References

  • Bartholin L, Maguer-Satta V, Hayette S, Martel S, Gadoux M, Bertrand S, Corbo L, Lamadon C, Morera A, Magaud J, Rimokh R . 2001 Oncogene 20: 5409–5419

  • Bitzer M, von Gersdorff G, Liang D, Dominguez-Rosales A, Beg AA, Rojkind M, Bottinger EP . 2000 Genes Dev. 14: 187–197

  • Brodin G, Ahgren A, ten Dijke P, Heldin CH, Heuchel R . 2000 J. Biol. Chem. 275: 29023–29030

  • de Winter JP, ten Dijke P, de Vries CJ, van Achterberg TA, Sugino H, de Waele P, Huylebroeck D, Verschueren K, van den Eijnden-van Raaij AJ . 1996 Mol. Cell. Endocrinol. 116: 105–114

  • Denissova NG, Pouponnot C, Long J, He D, Liu F . 2000 Proc. Natl. Acad. Sci. USA 97: 6397–6402

  • Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM . 1998 EMBO J. 17: 3091–3100

  • DePaolo LV . 1997 Proc. Soc. Exp. Biol. Med. 214: 328–339

  • Derynck R, Zhang Y, Feng XH . 1998 Cell 95: 737–740

  • Fainsod A, Deissler K, Yelin R, Marom K, Epstein M, Pillemer G, Steinbeisser H, Blum M . 1997 Mech. Dev. 63: 39–50

  • Gamer LW, Wolfman NM, Celeste AJ, Hattersley G, Hewick R, Rosen V . 1999 Dev. Biol. 208: 222–232

  • Gazzerro E, Gangji V, Canalis E . 1998 J. Clin. Invest. 102: 2106–2114

  • Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone Jr MA, Wrana JL, Falb D . 1997 Cell 89: 1165–1173

  • Hayette S, Gadoux M, Martel S, Bertrand S, Tigaud I, Magaud JP, Rimokh R . 1998 Oncogene 16: 2949–2954

  • Iemura S, Yamamoto TS, Takagi C, Uchiyama H, Natsume T, Shimasaki S, Sugino H, Ueno N . 1998 Proc. Natl. Acad. Sci. USA 95: 9337–9342

  • Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K . 1997 Nature 389: 622–626

  • Lagna G, Hata A, Hemmati-Brivanlou A, Massague J . 1996 Nature 383: 832–836

  • Lebrun JJ, Takabe K, Chen Y, Vale W . 1999 Mol. Endocrinol. 13: 15–23

  • Maguer-Satta V, Bartholin L, Jeanpierre S, Gadoux M, Bertrand S, Martel S, Magaud JP, Rimokh R . 2001 Exp. Hematol. 29: 301–308

  • Massague J, Wotton D . 2000 EMBO J. 19: 1745–1754

  • Moustakas A, Kardassis D . 1998 Proc. Natl. Acad. Sci. USA 95: 6733–6738

  • Nagarajan RP, Zhang J, Li W, Chen Y . 1999 J. Biol. Chem. 274: 33412–33418

  • Nakamura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H . 1990 Science 247: 836–838

  • Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P . 1997 Nature 389: 631–635

  • Pereira RC, Economides AN, Canalis E . 2000 Endocrinology 141: 4558–4563

  • Phillips DJ . 2000 Bioessays 22: 689–696

  • Phillips DJ, de Kretser DM . 1998 Front. Neuroendocrinol. 19: 287–322

  • Piek E, Heldin CH, Ten Dijke P . 1999 Faseb J. 13: 2105–2124

  • Reddi AH . 2001 Arthritis Res. 3: 1–5

  • Russell CE, Hedger MP, Brauman JN, de Kretser DM, Phillips DJ . 1999 Mol. Cell. Endocrinol. 148: 129–136

  • Schwall RH, Robbins K, Jardieu P, Chang L, Lai C, Terrell TG . 1993 Hepatology 18: 347–356

  • Shimasaki S, Koga M, Esch F, Cooksey K, Mercado M, Koba A, Ueno N, Ying SY, Ling N, Guillemin R . 1988 Proc. Natl. Acad. Sci. USA 85: 4218–4222

  • Smith WC . 1999 Trends Genet. 15: 3–5

  • Takase M, Imamura T, Sampath TK, Takeda K, Ichijo H, Miyazono K, Kawabata M . 1998 Biochem. Biophys. Res. Commun. 244: 26–29

  • ten Dijke P, Miyazono K, Heldin CH . 2000 Trends Biochem. Sci. 25: 64–70

  • Tsuchida K, Arai KY, Kuramoto Y, Yamakawa N, Hasegawa Y, Sugino H . 2000 J. Biol. Chem. 275: 40788–40796

  • Ulloa L, Doody J, Massague J . 1999 Nature 397: 710–713

  • Vindevoghel L, Lechleider RJ, Kon A, de Caestecker MP, Uitto J, Roberts AB, Mauviel A . 1998 Proc. Natl. Acad. Sci. USA 95: 14769–14774

  • Wrana JL . 2000 Cell 100: 189–192

  • Yamashita T, Takahashi S, Ogata E . 1992 Blood 79: 304–307

  • Yasuda H, Mine T, Shibata H, Eto Y, Hasegawa Y, Takeuchi T, Asano S, Kojima I . 1993 J. Clin. Invest. 92: 1491–1496

  • Ying SY, Zhang Z, Furst B, Batres Y, Huang G, Li G . 1997 Proc. Soc. Exp. Biol. Med. 214: 114–122

  • Yu J, Dolter KE . 1997 Cytokines Cell. Mol. Ther. 3: 169–177

  • Zhang Y, Feng X, We R, Derynck R . 1996 Nature 383: 168–172

  • Zhang YQ, Kanzaki M, Shibata H, Kojima I . 1997 Biochim. Biophys. Acta 1354: 204–210

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Acknowledgements

This study was supported by grants from INSERM, the Association pour la Recherche contre le Cancer, the Ligue contre le Cancer (Comités du Rhône et de la Saône et Loire). L Bartholin holds a doctoral fellowship from the Ligue contre le Cancer, Comité de la Haute Savoie. We would like to thank JM Gauthier for providing the (CAGA)9-MLP-Luc reporter vector, P ten Dijke for the mammalian expression vectors encoding the flag-tagged human Smad2, Smad3, Smad4 and Smad7, and R Derynck for the mammalian expression vectors encoding human dominant-negative Smad3 and Smad4. We would also like to thank MJ N'Guyen and C Lamadon for their technical assistance.

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  1. Laurent Bartholin and Véronique Maguer-Satta: L Bartholin and V Maguer-Satta contributed equally to this work

Authors and Affiliations

  1. INSERM U453, Centre Léon Bérard, 69373 Lyon, France

    Laurent Bartholin, Véronique Maguer-Satta, Sandrine Hayette, Sylvie Martel, Laura Corbo, Jean-Pierre Magaud & Ruth Rimokh

  2. Laboratoire de Cytogénétique Moléculaire, Hôpital Edouard Herriot, 69437 Lyon, France

    Sandrine Hayette, Mylène Gadoux & Jean-Pierre Magaud

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  1. Laurent Bartholin
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  2. Véronique Maguer-Satta
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Correspondence to Ruth Rimokh.

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Bartholin, L., Maguer-Satta, V., Hayette, S. et al. Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function. Oncogene 21, 2227–2235 (2002). https://doi.org/10.1038/sj.onc.1205294

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