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Molecular and Cellular Biology, June 2003, p. 4187-4198, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4187-4198.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of Subnuclear Localization Is Associated with a Mechanism for Nuclear Receptor Corepression by RIP140

Hiroshi Tazawa,1 Waffa Osman,1 Yutaka Shoji,1 Eckardt Treuter,2 Jan-Åke Gustafsson,1,2 and Johanna Zilliacus1*

Departments of Medical Nutrition,1 Biosciences, Karolinska Institutet, Novum, S-141 86 Huddinge, Sweden2

Received 5 July 2002/ Returned for modification 23 October 2002/ Accepted 31 March 2003

Regulation of gene transcription by nuclear receptors involves association with numerous coregulators. Receptor-interacting protein 140 (RIP140) is a corepressor that negatively regulates the ligand-induced activity of several nuclear receptors, including the glucocorticoid receptor (GR). In the present study, we have characterized the role of the intranuclear localization of RIP140 in its corepressor activity. In the absence of ligand-activated GR, RIP140 is localized in small nuclear foci targeted by a 40-amino-acid-long sequence. Although the focus-targeting domain overlaps with a binding sequence for the corepressor CtBP (C-terminal binding protein), interaction with CtBP is not involved in the localization. RIP140 foci do not correspond to PML bodies but partly colocalize with domains harboring the corepressor SMRT. Upon ligand binding, GR and RIP140 are redistributed to large nuclear domains distinct from the RIP140 foci. The redistribution requires regions of RIP140 with corepressor activity, as well as the DNA-binding domain of GR. Furthermore, we show that full RIP140 corepressor activity is contributed both by C-terminal receptor-binding LXXLL motifs and interaction with the CtBP corepressor. In conclusion, our results suggest that the corepressor function of RIP140 is multifaceted and involves binding to nuclear receptors, as well as additional functions mediated by the formation and intranuclear relocalization of a repressive protein complex.

* Corresponding author. Mailing address: Department of Medical Nutrition, Karolinska Institutet, Novum, S-141 86 Huddinge, Sweden. Phone: 46 8 58583737. Fax: 46 8 7116659. E-mail: johanna.zilliacus{at}mednut.ki.se.

Molecular and Cellular Biology, June 2003, p. 4187-4198, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4187-4198.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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