Unliganded thyroid hormone receptor beta1 inhibits proliferation of murine fibroblasts by delaying the onset of the G1 cell-cycle signals.
Thyroid hormone receptors (TRs) are members of the ligand-inducible transcription factor superfamily. The two major functional TRs (alpha1 and beta1) 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 TRbeta1 expression, in the absence of hormone, provokes a proliferation arrest in G0/G1, lengthening the cycling time. Upon serum stimulation TRbeta1-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 TRbeta1 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 TRbeta1 participates in the molecular mechanisms that control cell proliferation. The unliganded TRbeta1 impairs the normal induction of the G1/S cycle regulators preventing progression into the S phase.
Porlan
Eva
E
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas--Universidad Autónoma de Madrid, Arturo Duperier, 4, Madrid 28029, Spain.
Vega
Sonia
S
Iglesias
Teresa
T
Rodríguez-Peña
Angeles
A
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology*; D017931:DNA Primers; D005347:Fibroblasts / Q000166:cytology; D005434:Flow Cytometry; D016193:G1 Phase; D047468:Immunoprecipitation; D008024:Ligands; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D041701:Swiss 3T3 Cells; D037042:Thyroid Hormone Receptors beta / Q000502:physiology*
D017931:DNA Primers; D008024:Ligands; D037042:Thyroid Hormone Receptors beta