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FLRG, an activin-binding protein, is a new target of TGFβ transcription activation through Smad proteins

Oncogene volume 20, pages 5409–5419 (2001)Cite this article

Abstract

The FLRG gene encodes a secreted glycoprotein that binds to activin and is highly homologous to follistatin, an activin ligand. We cloned the promoter region of the human FLRG gene, and defined the minimal region necessary for transcription activation in a reporter-system assay. We showed that the fragment between positions −130 and +6, which consists of multiple consensus Sp1-binding sites, is required for the constitutive expression of the FLRG gene. We demonstrate here that FLRG mRNA expression is rapidly induced by TGFβ or by transfection with Smad protein expression vectors in human HepG2 cells. We investigated the transcription-regulation mechanism of FLRG expression in HepG2 cells following treatment with TGFβ. By deletion and point-mutation analysis of the FLRG promoter, we identified a Smad-binding element involved in the TGFβ-inducible expression of the FLRG gene. Moreover, transactivation of the FLRG promoter by TGFβ was compromised by dominant-negative mutants of Smad3 and Smad4 proteins. In addition, gel electrophoresis mobility-shift assays demonstrated the specific interaction of Smad3 and Smad4 proteins with the Smad-binding element consensus motif found in the FLRG promoter. Taken together, our data imply that Smad proteins participate in the regulation of expression of FLRG, a new target of TGFβ transcription activation.

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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). We would like to thank JM Gauthier for providing the pGL3-MLP plasmid, P ten Dijke for the mammalian expression vectors encoding the flag-tagged human Smad2, Smad3 and Smad4, R Derynck for the mammalian expression vectors encoding human dominant-negative Smad3 (Smad3ΔC) and Smad4 (Smad4ΔC), and A Mauviel for bacterial vectors encoding GST-Smad proteins. We would like to thank MJ N'Guyen for her technical assistance. L Bartholin held a doctoral fellowship from the Ligue contre le Cancer, comité de la Haute Savoie.

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Authors and Affiliations

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

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

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

    Sandrine Hayette, Mylène Gadoux, Suzanne Bertrand & Jean-Pierre Magaud

  3. Unité INSERM U329, Hôpital Debrousse, Lyon, 69322, France

    Anne-Marie Morera

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  1. Laurent Bartholin
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Correspondence to Ruth Rimokh.

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Bartholin, L., Maguer-Satta, V., Hayette, S. et al. FLRG, an activin-binding protein, is a new target of TGFβ transcription activation through Smad proteins. Oncogene 20, 5409–5419 (2001). https://doi.org/10.1038/sj.onc.1204720

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