Thyroid hormone receptor-beta (TR beta 1) impairs cell proliferation by the transcriptional inhibition of cyclins D1, E and A2.
Thyroid hormone receptor-beta1 (TRbeta1) belongs to the ligand-inducible transcription factor superfamily. We have previously described that stable TRbeta1 expression impairs fibroblast proliferation diminishing levels and activity of the main regulators of the G(1)/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 TRbeta1 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 TRbeta1 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 TRbeta1 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-TRbeta1 exerts its antiproliferative action through a mechanism that could constitute a model by which other nuclear receptors may control cell division.
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
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Porlan
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Vidaurre
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Rodríguez-Peña
D000818:Animals; D049109:Cell Proliferation; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D056751:Cyclin A2; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation / Q000502:physiology*; D006131:Growth Inhibitors / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D041701:Swiss 3T3 Cells; D037042:Thyroid Hormone Receptors beta / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
C508184:CCNA2 protein, mouse; D019925:Cyclin A; D056751:Cyclin A2; D019927:Cyclin E; D016213:Cyclins; D006131:Growth Inhibitors; D037042:Thyroid Hormone Receptors beta; D019938:Cyclin D1