Polarity-specific activities of retinoic acid receptors determined by a co-repressor.
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.
Kurokawa
R
R
Department of Medicine, University of California, San Diego, La Jolla 92093-0651, USA.
Söderström
M
M
Hörlein
A
A
Halachmi
S
S
Brown
M
M
Rosenfeld
M G
MG
Glass
C K
CK
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000378:metabolism*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors