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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR ENDOCRINOLOGY; v. 29, n. 2, p. 258-273, FEB 2015.
• Citações Web of Science: 9

Resumo

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)

• Processo FAPESP: 11/23725-5 - Validação de elementos responsivos aos receptores nucleares Coup-TFII no promotor do gene SMyHC3
• Beneficiário: Juliana Fattori
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 11/23659-2 - Interação entre os receptores nucleares TR (receptores de hormônios tireoidianos), PPAR (receptores ativadores da proliferação dos peroxissomos) e outras proteínas celulares
• Beneficiário: Jéssica Christina Lóis de Oliveira Campos
• Linha de fomento: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 13/08743-2 - Indentificação e caracterização de novas interações entre os receptores de hormônios tireoidianos e proteínas
• Beneficiário: Ana Carolina Migliorini Figueira
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/04019-5 - Expressão e purificação de receptores nucleares e proteínas associadas
• Beneficiário: Mariela Thim Vitorino
• Linha de fomento: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico
• Processo FAPESP: 10/17048-8 - Regulação da transativação e transrepressão gênica mediada por receptores nucleares
• Beneficiário: Ana Carolina Migliorini Figueira
• Linha de fomento: Auxílio à Pesquisa - Regular