Polarity-specific activities of retinoic acid receptors determined by a co-repressor

• DOI: 10.1038/377451a0
• Publication Date: 2003-06-12T23:57:07Z
• Authors: Riki Kurokawa; Mats Söderström; Andreas Hörlein; Shlomit Halachmi; Myles Brown; Michael G. Rosenfeld; Christopher K. Glass
• Keywords: Transcriptional Activation; 0303 health sciences; Binding Sites; Base Sequence; Receptors, Retinoic Acid; Molecular Sequence Data; Nuclear Proteins; Regulatory Sequences, Nucleic Acid; Cell Line; Repressor Proteins; 03 medical and health sciences; Retinoid X Receptors; Allosteric Regulation; Mutagenesis, Site-Directed; Humans; Nuclear Receptor Co-Repressor 1; Amino Acid Sequence; Transcription Factors

Retinoic acid receptors (RARs) and retinoid-X receptors (RXRs) activate or repress transcription by binding as heterodimers to DNA-response elements that generally consist of two direct repeat half-sites of consensus sequence AGGTCA. On response elements consisting of direct repeats spaced by five base pairs (DR + 5 elements), RAR/RXR heterodimers activate transcription in response to RAR-specific ligands, such as all-trans-retinoic acid (RA). In contrast, on elements consisting of direct repeats spaced by one base pair (DR + 1 elements), RAR/RXR heterodimers exhibit little or no response to activating ligands and repress RXR-dependent transcription. Here we show that ligand-dependent transactivation by RAR on DR + 5 elements requires the dissociation of a new nuclear receptor co-repressor, N-CoR, and recruitment of the putative co-activators p140 and p160. Surprisingly, on DR + 1 elements, N-CoR remains associated with RAR/RXR heterodimers even in the presence of RAR ligands, resulting in constitutive repression. These observations indicate that DNA-response elements can allosterically regulate RAR-co-repressor interactions to determine positive or negative regulation of gene expression.