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Thyroid hormone receptor-β (TRβ1) impairs cell proliferation by the transcriptional inhibition of cyclins D1, E and A2

Oncogene volume 27, pages 2795–2800 (2008)Cite this article

Abstract

Thyroid hormone receptor-β1 (TRβ1) belongs to the ligand-inducible transcription factor superfamily. We have previously described that stable TRβ1 expression impairs fibroblast proliferation diminishing levels and activity of the main regulators of the G1/S transition. To unmask the underlying molecular mechanism of this action, we have investigated the expression of cyclin D1, E and A2 upon serum stimulation in TRβ1 expressing cells, finding a strong downregulation of their mRNAs, concomitant with low protein levels. The inhibition of the transcriptional activation in response to serum of these cyclins is differently exerted. For cyclin D1, we demonstrate that TRβ1 represses its promoter as a consequence of the downregulation of c-jun levels, diminished AP-1 activation and loss of c-jun recruitment to its binding sites on cyclin D1 promoter. For cyclin E and A2, it is the impairment of the cyclinD/Rb/E2F pathway by TRβ1 that prevents the activation of these two E2F target genes. Indeed, recruitment of E2F-1 to cyclin A2 promoter could not be detected. In summary, we propose that apo-TRβ1 exerts its antiproliferative action through a mechanism that could constitute a model by which other nuclear receptors may control cell division.

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Acknowledgements

We thank Dr MR Campanero and Dr M Diaz-Guerra for critically reading the manuscript and Dr T Iglesias for helpful discussions and valuable comments. We are also indebted to Dr MR Campanero, Dr R Pestell and Dr V Andrés for E2F and cyclin D1 and A2 reporter plasmids and Dr P Maruvada for TRβ mutants. This work was supported by grants to AR-P from Dirección General de Investigación Científica y Técnica (MEC-BFU2004-01498). EP is supported by a grant-associated contract, and OGV is recipient of a pre-doctoral fellowship from Ministerio de Educación y Ciencia associated to the MEC grant.

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  1. Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain

    E Porlan, O G Vidaurre & A Rodríguez-Peña

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  1. E Porlan
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  2. O G Vidaurre
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Correspondence to A Rodríguez-Peña.

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Porlan, E., Vidaurre, O. & Rodríguez-Peña, A. Thyroid hormone receptor-β (TRβ1) impairs cell proliferation by the transcriptional inhibition of cyclins D1, E and A2. Oncogene 27, 2795–2800 (2008). https://doi.org/10.1038/sj.onc.1210936

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