Flrg, an activin-binding protein, is a new target of tgfβ transcription activation through smad proteins

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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FORTILIN INTERACTS WITH TGF-Β1 AND PREVENTS TGF-Β RECEPTOR ACTIVATION Article Open access 23 February 2022 REFERENCES * Brodin G, Ahgren A, ten Dijke P, Heldin CH, Heuchel R . 2000 _J. Biol.

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Zhang YQ, Kanzaki M, Shibata H, Kojima I . 1997 _Biochim. Biophys. Acta._ 1354: 204–210 Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * Laboratoire de Cytogénétique Moléculaire, Hôpital

Edouard Herriot, Lyon, 69437, France Sandrine Hayette, Mylène Gadoux, Suzanne Bertrand & Jean-Pierre Magaud * Unité INSERM U329, Hôpital Debrousse, Lyon, 69322, France Anne-Marie Morera

Authors * Laurent Bartholin View author publications You can also search for this author inPubMed Google Scholar * Véronique Maguer-Satta View author publications You can also search for

this author inPubMed Google Scholar * Sandrine Hayette View author publications You can also search for this author inPubMed Google Scholar * Sylvie Martel View author publications You can

also search for this author inPubMed Google Scholar * Mylène Gadoux View author publications You can also search for this author inPubMed Google Scholar * Suzanne Bertrand View author

publications You can also search for this author inPubMed Google Scholar * Laura Corbo View author publications You can also search for this author inPubMed Google Scholar * Christine

Lamadon View author publications You can also search for this author inPubMed Google Scholar * Anne-Marie Morera View author publications You can also search for this author inPubMed Google

Scholar * Jean-Pierre Magaud View author publications You can also search for this author inPubMed Google Scholar * Ruth Rimokh View author publications You can also search for this author

inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Ruth Rimokh. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 13 December 2000 * Revised: 31 May 2001 * Accepted: 14 June 2001 * Published: 12 September 2001 * Issue Date: 06

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shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * FLRG * TGFβ * Smad * activin *

follistatin