Thyroid hormone receptor-[beta] (TR[beta]1) impairs cell proliferation by the transcriptional inhibition of cyclins D1, E and A2

Thyroid hormone receptor-[beta]1 (TR[beta]1) belongs to the ligand- inducible transcription factor superfamily. We have previously described that stable TR[beta]1 expression impairs fibroblast proliferation diminishing levels and activity of the main regulators of the G sub(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 TR[beta]1 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 TR[beta]1 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 TR[beta]1 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-TR[beta]1 exerts its antiproliferative action through a mechanism that could constitute a model by which other nuclear receptors may control cell division.