title: Synthetic retinoids dissociate coactivator binding from corepressor release.
abstract: The ligand-activated retinoid receptors RXR and RAR control development, homeostasis and disease by regulating transcription of retinoic acid (RA) responsive target genes or crosstalk with other signalling pathways. According to the current model ligand-binding triggers an exchange between corepressor- and coactivator-complexes that inhibit or potentiate transcription by deacetylating and acetylating nucleosomal histones, respectively. Additional cofactors may modify the transcriptional regulatory process by linking liganded retinoid receptors to structural components of chromatin or protein degradation. The desire to specifically influence defined events in RA-signalling, while others are left unaffected, motivated the synthesis of retinoid X receptors (RXR)- and retinoid acid receptors (RAR) isoform-selective retinoids. The present study investigates the potential of RARalpha isotype-specific synthetic agonists and antagonists to separate the processes of coactivator recruitment and corepressor release. The synthetic retinoids studied fall into four categories, two of which work according the above model, since they induce surfaces within the RARalpha ligand binding domain (LBD) suitable for either corepressor or coactivator interaction; these retinoids act as pure antagonists and pure agonists, respectively. In contrast, another type of retinoid induces a structure that allows for both, the interaction with corepressors and coactivators (partial RARalpha agonist), and exerts a cell context-specific (ant)agonistic activity. Finally, another type of retinoid, which cannot activate transcription itself but renders heterodimeric RARalpha permissive for signaling by RXR agonists inhibits both, corepressor and coactivator interaction (partial antagonist). Moreover, this retinoid discriminates between the nuclear corepressors SMRT and NCoR, since it efficiently dissociates SMRT but not NCoR from the RARalpha LBD.
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, Laboratory of Neurobiology, University of Mainz, Duesberg Weg 6, D-55099 Mainz, Germany. zechel@mail.uni-mainz.de
authors.forename: Christina
authors.initials: C
authors.lastname: Zechel
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D020033:Protein Isoforms; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D020033:Protein Isoforms; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; C082925:retinoic acid receptor beta