Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2013) 32 P722 | DOI: 10.1530/endoabs.32.P722

ECE2013 Poster Presentations Nuclear receptors and signal transduction (7 abstracts)

The thyroid hormone receptors inhibit invasive and fibrotic responses to TGFβ by transcriptional cross-talk with smad-transcription factors

Elvira Alonso-Merino 1 , Rosa M Martín-Orozco 1 , Lidia Ruiz-Llorente 1 , Luisa Fernanda Fanjul-Rodriguez 1 , Olaia Martínez-Igesias 1 , Juan Pedro Velasco-Martín 2 , Javier Regadera 2 & Ana Aranda 1


1Instituto De Investigaciones Biomédicas Alberto Sols Csic-Uam, Madrid, Spain; 2Department of Anatomy, Histology and Neuroscience, School of Medicine, Uam, Madrid, Spain.

Transforming growth factor β (TGFβ) signals through activation of Smad transcription factors, which bind to Smad binding elements (SBEs) in target genes. TGFβ can promote cancer cell proliferation and invasion, and plays a key role in the pathogenesis of scleroderma and other fibrotic disorders. We have previously shown that the thyroid hormone receptors (TRs) can block tumor growth and invasion. We now have analyzed the possibility that TRs could antagonize TGFβ-ependent responses. We found that liganded TRs block transactivation of SBE-containing reporter plasmids by TGFβ, and repress transcription of endogenous TGFβ target genes. The thyroid hormone T3 reduces Smad phosphorylation by TGFβ and causes a limited inhibition of Smads translocation to the nucleus. There is a direct and constitutive protein-protein interaction between TR and Smad transcription factors that could be involved in the observed effects. In chromatin immunoprecipitation assays (ChIP) with SBE-containing promoters, T3 inhibits TGFβ-dependent recruitment of Smads, reduces acetylated histones and induces recruitment of histone decetylase 3 (HDAC3). The hormone is also able to block TGFβ-dependent proliferation and migration of cultured cancer cells. The potential anti-fibrotic effect of the TRs was investigated in mice using a model of skin fibrosis induced by subcutaneous injections of bleomycin. In euthyroid mice bleomycin caused a significant increase in dermal thickness, hair loss and high packaging of collagen fibers, characteristic of areas of dermal scleroderma and fibrosis. Topical application of T3 significantly attenuated fibrosis, with a decrease of dermis thickness, reduced compactation of bundle collagen fibers and more extracellular matrix, associated to a low collagenization of subcutaneous cellular tissue. These results demonstrate that T3 blocks transcriptional responses to TGFβ, and suggest that some of the actions of the thyroid hormone receptors, both in vivo and in cultured cells, can involve repression of the activity of the TGFβ signalling pathway.

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