title: RXR agonist modulates TR: corepressor dissociation upon 9-cis retinoic acid treatment.
abstract: Transcriptional regulation controlled by thyroid hormone receptor (TR) drives events such as development, differentiation, and metabolism. TRs may act either as homodimers or as heterodimers with retinoid X receptor (RXR). Thyroid hormone T3 preferentially binds TR-RXR heterodimers, which activate transcription through coactivator recruitment. However, it is unclear whether TR-RXR heterodimers may also be responsive to the canonical RXR agonist 9-cis retinoic acid (9C) in the context of physiological gene regulation. New structural studies suggest that 9C promotes the displacement of bound coactivators from the heterodimer, modifying TR-RXR activity. To shed light on the molecular mechanisms that control TR-RXR function, we used biophysical approaches to characterize coregulator recruitment to TR-TR or to TR-RXR in the presence of T3 and/or 9C as well as cell-based assays to establish the functional significance of biophysical findings. Using cell-based and fluorescence assays with mutant and wild-type TR, we show that 9C does indeed have a function in the TR-RXR heterodimer context, in which it induces the release of corepressors. Furthermore, we show that 9C does not promote detectable conformational changes in the structure of the TR-RXR heterodimer and does not affect coactivator recruitment. Finally, our data support the view that DNA binding domain and Hinge regions are important to set up NR-coactivator binding interfaces. In summary, we showed that the RXR agonist 9C can regulate TR function through its modulation of corepressor dissociation.
authors.affiliation: Centro Nacional de Pesquisa em Energia e Materiais (J.F., J.L.O.C., T.R.D., L.M.A., M.T.V., J.X.-N., A.C.M.F.), Laboratório Nacional de Biociências, Campinas SP, 13083-970, Brazil; and Instituto de Física de São Carlos (I.P.), Universidade de São Paulo, São Carlos SP, 13560-970, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Fattori
authors.forename: Jéssica L O
authors.initials: JL
authors.lastname: Campos
authors.forename: Tábata R
authors.initials: TR
authors.lastname: Doratioto
authors.forename: Lucas M
authors.initials: LM
authors.lastname: Assis
authors.forename: Mariela T
authors.initials: MT
authors.lastname: Vitorino
authors.forename: Igor
authors.initials: I
authors.lastname: Polikarpov
authors.forename: José
authors.initials: J
authors.lastname: Xavier-Neto
authors.forename: Ana Carolina M
authors.initials: AC
authors.lastname: Figueira
mesh_terms: D000077556:Alitretinoin; D016880:Anisotropy; D002850:Chromatography, Gel; D002942:Circular Dichroism; D056970:Co-Repressor Proteins / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D000067493:Dynamic Light Scattering; D005453:Fluorescence; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000819:agonists*; D053838:Scattering, Small Angle; D015533:Transcriptional Activation / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D014364:Tryptophan / Q000378:metabolism; D014461:Ultracentrifugation; D014961:X-Ray Diffraction
chemical_list: D056970:Co-Repressor Proteins; D046912:Multiprotein Complexes; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D000077556:Alitretinoin; D014212:Tretinoin; D014364:Tryptophan; D004247:DNA