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Molecular and Cellular Biology, June 2008, p. 3817-3829, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.01909-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Vitamin D-Dependent Recruitment of Corepressors to Vitamin D/Retinoid X Receptor Heterodimers

Ruth Sánchez-Martínez, Alberto Zambrano, Ana I. Castillo, and Ana Aranda^*

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cieníficas and Universidad Autónoma de Madrid, Madrid, Spain

Received 23 October 2007/ Returned for modification 11 December 2007/ Accepted 14 March 2008

Transcriptional regulation by nuclear receptors is mediated by recruitment of coactivators and corepressors. In the classical model, unliganded nonsteroidal receptors bind corepressors, such as the silencing mediator of thyroid and retinoid receptors (SMRT) or nuclear corepressor (NCoR), that are released upon ligand binding. We show here that, unlike other receptors, the heterodimer of the vitamin D receptor (VDR) with the retinoid X receptor (RXR) recruits NCoR and SMRT strictly in a VDR agonist-dependent manner. Binding of an agonist to VDR allows its partner receptor, RXR, to bind the corepressors. The RXR ligand has the opposite effect and induces corepressor release from the heterodimer. 1,25-Dihydroxy-vitamin D₃ (VD3) causes recruitment of SMRT and NCoR to a VDR target promoter. Down-regulation of corepressors by means of small interfering RNA enhances transcriptional responses to VD3. These data reveal a new paradigm of SMRT and NCoR binding to nuclear receptors and demonstrate that these corepressors can function as physiological negative regulators of VD3-mediated transcription.

Published ahead of print on 24 March 2008.

These authors contributed equally to this work.