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Unliganded thyroid hormone receptor β1 inhibits proliferation of murine fibroblasts by delaying the onset of the G1 cell-cycle signals

Oncogene volume 23, pages 8756–8765 (2004)Cite this article

Abstract

Thyroid hormone receptors (TRs) are members of the ligand-inducible transcription factor superfamily. The two major functional TRs (α1 and β1) have different spatial and temporal expression patterns and specific physiological functions for these isoforms are now starting to emerge. By expressing these TR isoforms individually in Swiss 3T3 fibroblasts, we found that TRβ1 expression, in the absence of hormone, provokes a proliferation arrest in G0/G1, lengthening the cycling time. Upon serum stimulation TRβ1-expressing cells showed a marked delay in the induction of cyclins D and E, in the phosphorylation of retinoblastoma protein, and in the activation of cyclin-dependent kinase 2, accompanied by increased levels of cyclin-dependent kinase inhibitor p27Kip1. Accordingly, serum-stimulated E2F-1 transcriptional activity was repressed by TRβ1 in transient transfection experiments. Analysis of the receptor domains required for this effect confirmed that there is no need for a functional ligand-binding domain while the DNA-binding domain is essential. In this work, we demonstrate for the first time that TRβ1 participates in the molecular mechanisms that control cell proliferation. The unliganded TRβ1 impairs the normal induction of the G1/S cycle regulators preventing progression into the S phase.

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Abbreviations

T3:

triiodothyronine

T4:

tetraiodothyronine

TR:

thyroid hormone nuclear receptor

TRα1:

thyroid hormone receptor-α1

TRβ1:

thyroid hormone receptor-β1

Cdk:

cyclin-dependent kinase

Cki:

cyclin-dependent kinase inhibitor

Rb:

retinoblastoma susceptibility protein

BrdU:

5-bromo-2′-deoxyuridine

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Acknowledgements

We thank Dr LL Sarliève for the kind gift of the antibodies against the TRs, Dr MR Campanero for E2F reporter plasmids, and Dr P Maruvada for the TRβ1 mutants. We are especially grateful to Dr Simon Bartlett for critically reading the manuscript and for his valuable comments, and to all members of the laboratory for helpful discussions. This work was supported by grants to AR-P from Dirección General de Investigación Científica y Técnica (M.C.Y.T: SAF2001-1624). SV was supported by a fellowship from Comunidad Autónoma de Madrid. EP is recipient of a predoctoral fellowship from Ministerio de Ciencia y Tecnología associated to the M.C.Y.T. grant.

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  1. Sonia Vega

    Present address: Instituto Cajal, Consejo Superior de Investigaciones Científicas, Dr Arce, 37, Madrid, 28002, Spain

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas – Universidad Autónoma de Madrid, Arturo Duperier, 4, Madrid, 28029, Spain

    Eva Porlan, Sonia Vega, Teresa Iglesias & Angeles Rodríguez-Peña

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  1. Eva Porlan
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Correspondence to Angeles Rodríguez-Peña.

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Porlan, E., Vega, S., Iglesias, T. et al. Unliganded thyroid hormone receptor β1 inhibits proliferation of murine fibroblasts by delaying the onset of the G1 cell-cycle signals. Oncogene 23, 8756–8765 (2004). https://doi.org/10.1038/sj.onc.1208126

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