POLARITY-SPECIFIC ACTIVITIES OF RETINOIC ACID RECEPTORS DETERMINED BYA CO-REPRESSOR

RETINOIC acid receptors (RARs) and retinoid-X receptors (RXRs) activat e or repress transcription by binding as heterodimers to DNA-response elements that generally consist of two direct repeat half-sites of con sensus sequence AGGTCA (reviewed in ref. 1). On response elements cons isting of direct repeats spaced by five base pairs (DR + 5 elements), RAR/RXR heterodimers activate transcription in response to RAR-specifi c ligands, such as all-trans-retinoic acid (RA)(2). In contrast, on el ements consisting of direct repeats spaced by one base pair (DR + 1 el ements), RAR/RXR heterodimers exhibit little or no response to activat ing ligands and repress RXR-dependent transcription(3). Here we show t hat ligand-dependent transactivation by RAR on DR + 5 elements require s the dissociation of a new nuclear receptor co-repressor, N-CoR, and recruitment of the putative co-activators p140 and p160 (refs 4, 5). S urprisingly, on DR + 1 elements, N-CoR remains associated with RAR/RXR heterodimers even in the presence of RAR ligands, resulting in consti tutive repression. These observations indicate that DNA-response eleme nts can allosterically regulate RAR-co-repressor interactions to deter mine positive or negative regulation of gene expression.