ECE2014 Poster Presentations Nuclear receptors and signal transduction (4 abstracts)
Thyroid receptors antagonizes TGFβ actions in vivo and in culture cells
Elvira Alonso Merino 1 , Rosa M Martín Orozco 1 , Lidia Ruíz Llorente 1 , Luisa Fernanda Fanjul Rodríguez 1 , Olaia Martínez-Iglesias 1 , Juan Pedro Velasco-Martín 2 , Javier Regadera 2 & Ana Aranda 1
1Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain; 2Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Transforming growth factor beta (TGFβ), which plays a key role in cancer and fibrotic disorders, mediates its actions mainly through activation of Smad transcription factors, which bind to Smad Binding Elements (SBEs) in target genes. We have previously observed that the thyroid hormone T3 blocks transactivation of SBE-containing reporter plasmids by TGFβ, and represses transcription of endogenous TGFβ target genes. We have now analysed the thyroid hormone receptor (TR) isoform as well as the receptor domains responsible for this transcriptional antagonism. In GH4C1 pituitary cells, the TRβ specific agonist GC1 is as potent as T3 to repress SMAD-dependent transactivation, showing that this isoform mediates the antagonism. However, expression of TRα in other cell types also mediates repression of TGFβ-dependent transactivation by T3. Therefore, both receptor isoforms can antagonize TFGβ actions. Using TRα and TRβ mutants we observed that the receptor DNA binding domain (DBD) is essential to carry out the repressive effect, whereas the ligand-dependent transcriptional activation domain responsible for coactivators binding appears to be dispensable. We also detected a direct interaction of TRα and TRβ with Smad 2/3 and Smad 4. The DBD plays an important role in this interaction, which is reversed by T3. In chromatin immunoprecipitation (ChIP) assays with SBE-containing promoters, T3 inhibits TGFβ-dependent recruitment of Smads. TRs bind to the SBE-containing regions and this interaction is also released by T3. We had observed that hyperthyroidism alleviates the fibrotic response induced by bleomycin in mice skin. We have now examined if TR signalling could also impact liver fibrogenesis. Indeed, 18-month-old knock-out mice lacking TRαand TRβ exhibited a spontaneous injury phenotype with increased collagen deposition, demonstrating that the endogenous receptors play a role in vivo as inhibitors of this TGFβ-dependent response.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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