title: The receptor-DNA complex determines the retinoid response: a mechanism for the diversification of the ligand signal.
abstract: To obtain insights into the principles governing the complex biological responses to retinoids, we have analyzed the ligand sensitivities of various retinoid receptor-DNA complexes. We find that different retinoid receptor heterodimers show distinct activation patterns with various response elements while a given heterodimer can be activated at different retinoic acid concentrations on different response elements. In vitro binding experiments suggest that the same retinoic acid receptor-retinoid X receptor (RAR-RXR) heterodimer can have different ligand affinities, depending on the response element it is bound to. The differential responses of a particular receptor heterodimer with various retinoic acid responsive elements can be enhanced through the use of conformationally restricted retinoids. RAR- and RXR-selective retinoids can also synergistically activate the receptor heterodimers, indicating that both partners in the heterodimer can contribute to ligand-induced transcriptional activation. However, the relative influence of the RAR or RXR partner is specific for each response element. Together, our data demonstrate that it is the receptor-DNA complex and not the receptor alone that determines the ligand response. This flexibility allows for a highly pleiotropic retinoid response. Furthermore, conformationally restricted retinoids can accentuate the differential responses and exhibit a certain degree of gene selectivity by differentially activating the RAR or RXR component in the context of a given response element.
authors: Sidney Kimmel Cancer Center, La Jolla, California 92037, USA.
authors: N
authors: N
authors: La Vista-Picard
authors: P D
authors: PD
authors: Hobbs
authors: M
authors: M
authors: Pfahl
authors: M I
authors: MI
authors: Dawson
authors: M
authors: M
authors: Pfahl
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000502:physiology*; D008024:Ligands; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000502:physiology*; D047488:Retinoid X Receptors; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D046911:Macromolecular Substances; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors