CIA, a Novel Estrogen Receptor Coactivator with a Bifunctional Nuclear Receptor Interacting Determinant

doi:10.1128/MCB.21.1.343-353.2001

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Molecular and Cellular Biology, January 2001, p. 343-353, Vol. 21, No. 1
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.1.343-353.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

CIA, a Novel Estrogen Receptor Coactivator with a Bifunctional Nuclear Receptor Interacting Determinant

Frédéric Sauvé,¹^,² Linda D. B. McBroom,¹ Josette Gallant,¹^,² Anna N. Moraitis,¹^,² Fernand Labrie,³ and Vincent Giguère¹^,²^,⁴^,^*

Molecular Oncology Group, McGill University Health Centre, Montréal, Québec H3A 1A1,¹ Departments of Biochemistry² and Medicine and Oncology,⁴ McGill University, Montréal, Québec H3G 1Y6, and Laboratory of Molecular Endocrinology, Laval University Medical Research Center and Laval University, Québec, Québec G1V 4G2,³ Canada

Received 26 May 2000/Returned for modification 10 July 2000/Accepted 9 October 2000

Coregulators for nuclear receptors (NR) are factors that either enhance or repress their transcriptional activity. Both coactivatorsand corepressors have been shown to use similar but functionallydistinct NR interacting determinants containing the core motifsLxxLL and $Phi$ xx $Phi$ $Phi$ , respectively. These interactions occur througha hydrophobic cleft located on the surface of the ligand-bindingdomain (LBD) of the NR and are regulated by ligand-dependent activationfunction 2 (AF-2). In an effort to identify novel coregulatorsthat function independently of AF-2, we used the LBD of the orphanreceptor RVR (which lacks AF-2) as bait in a yeast two-hybridscreen. This strategy led to the cloning of a nuclear proteinreferred to as CIA (coactivator independent of AF-2 function)that possesses both repressor and activator functions. Strikingly,we observed that CIA not only interacts with RVR and Rev-ErbA $alpha$ in a ligand-independent manner but can also form complexes withestrogen receptor alpha (ER $alpha$ ) and ER $beta$ in vitro and enhances ER $alpha$ transcriptional activity in the presence of estradiol (E₂). CIA-ER $alpha$ interactions were found to be independent of AF-2 and enhancedby the antiestrogens EM-652 and ICI 182,780 but not by 4-hydroxytamoxifenand raloxifene. We further demonstrate that CIA-ER $alpha$ interactionsrequire the presence within CIA of a novel bifunctional NR recognitiondeterminant containing overlapping LxxLL and $Phi$ xx $Phi$ $Phi$ motifs. Theidentification and functional characterization of CIA suggestthat hormone binding can create a functional coactivator interactioninterface in the absence of AF-2.

^* Corresponding author. Mailing address: Molecular Oncology Group, McGill University Health Centre, Royal Victoria HospitalPavilion, 687 Pine Ave. West, Montréal, Québec, Canada H3A 1A1.Phone: (514) 843-1479. Fax: (514) 843-1478. E-mail: vgiguere{at}dir.molonc.mcgill.ca.

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