Inactivation of the Nuclear Orphan Receptor COUP-TFII by Small Chemicals

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Le Guével, Rémy | Oger, Frederik | Martinez-Jimenez, Celia P. | Bizot, Maud | Gheeraert, Celine | Firmin, François | Ploton, Maheul | Kretova, Miroslava | Palierne, Gaëlle | Staels, Bart | Barath, Peter | Talianidis, Iannis | Lefebvre, Philippe | Eeckhoute, Jérôme | Salbert, Gilles

Edité par CCSD ; American Chemical Society -

International audience. Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan member of the nuclear receptor family of transcription factors whose activities are modulated upon binding of small molecules into an hydrophobic ligand-binding pocket (LBP). Although the LBP of COUP-TFII is filled with aromatic amino-acid side chains, alternative modes of ligand binding could potentially lead to regulation of the orphan receptor. Here, we screened a synthetic and natural compound library in a yeast one-hybrid assay and identified 4-methoxynaphthol as an inhibitor of COUP-TFII. This synthetic inhibitor was able to counteract processes either positively or negatively regulated by COUP-TFII in different mammalian cell systems. Hence, we demonstrate that the true orphan receptor COUP-TFII can be targeted by small chemicals which could be used to study the physiological functions of COUP-TFII or to counteract detrimental COUP-TFII activities in various pathological conditions.

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