A Permissive Retinoid X Receptor/Thyroid Hormone Receptor Heterodimer Allows Stimulation of Prolactin Gene Transcription by Thyroid Hormone and 9-cis-Retinoic Acid

Ana I. Castillo, Ruth Sánchez-Martínez, Jose L. Moreno, Olaia A. Martínez-Iglesias, Daniela Palacios, Ana Aranda

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

Heterodimers of the retinoid X receptor (RXR) with the thyroid hormone receptor (TR) are considered to be nonpermissive. It is believed that within these complexes RXR acts as a "silent partner." We demonstrate here that a permissive heterodimer mediates stimulation of prolactin expression by the thyroid hormone T3 and by 9-cis retinoic acid (9-cis-RA). A response element located in the prolactin distal enhancer mediates transactivation by both ligands in pituitary cells, and RXR recruits coactivators when bound to this element as a heterodimer with TR. Furthermore, transcription by the RXR agonist can be obtained in CV-1 cells only after overexpression of coactivators, and overexpression of corepressors inhibits the response in pituitary cells. Thus, cell type-specific differences in coregulator recruitment can determine the cellular response to both ligands. Coactivator recruitment by 9-cis-RA requires the ligand-dependent transactivation domains (AF-2) of both heterodimeric partners. Interestingly, the presence of the RXR ligand can overcome the deleterious effect of the AF-2 mutation E401Q on association with coactivators and transactivation. These results demonstrate an unexpected role for RXR in TRsignaling and show that in particular cellular environments this receptor can act as a "nonsilent" partner of TR, allowing stimulation by RXR agonists.
Lingua originaleEnglish
pagine (da-a)502-513
Numero di pagine12
RivistaMolecular and Cellular Biology
Volume24
DOI
Stato di pubblicazionePubblicato - 2004

Keywords

  • Cell differentiation
  • Lactotrope cells
  • Nuclear receptors
  • Transcriptional regulation

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