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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

RXR Agonist Modulates TR: Corepressor Dissociation Upon 9-cis Retinoic Acid Treatment

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Fattori, Juliana [1] ; Campos, Jessica L. O. [1] ; Doratioto, Tabata R. [1] ; Assis, Lucas M. [1] ; Vitorino, Mariela T. [1] ; Polikarpov, Igor [2] ; Xavier-Neto, Jose [1] ; Figueira, Ana Carolina M. [1]
Total Authors: 8
[1] Ctr Nacl Pesquisa Energia & Mat, Lab Nacl Biociencias, BR-13083970 Campinas, SP - Brazil
[2] Univ Sao Paulo, Inst Fis Sao Carlos, BR-13560970 Sao Carlos, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: MOLECULAR ENDOCRINOLOGY; v. 29, n. 2, p. 258-273, FEB 2015.
Web of Science Citations: 9

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. (AU)

FAPESP's process: 13/08743-2 - Identification and characterization of new interactions among thyroid hormone receptors and proteins
Grantee:Ana Carolina Migliorini Figueira
Support type: Regular Research Grants
FAPESP's process: 11/23659-2 - Interaction between nuclear receptors TR (thyroid hormone receptor), PPAR (Peroxissome Proliferator-Activated Receptor) and other cell proteins
Grantee:Jéssica Christina Lóis de Oliveira Campos
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 11/23725-5 - Validation of response elements for the nuclear receptors COUP-TFII in the SMyHC3 gene promoter
Grantee:Juliana Fattori
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 10/17048-8 - Regulation of genic transactivation and transrepression mediated by nuclear receptors
Grantee:Ana Carolina Migliorini Figueira
Support type: Regular Research Grants