Cyclin D1 Is a Ligand-independent Co-repressor for Thyroid Hormone Receptors.
Thyroid hormone receptors (TRs) are critical regulators of growth, differentiation, and homeostasis. TRs function by regulating the expression of thyroid hormone (T3) target genes in both ligand-dependent and -independent pathways. Distinct classes of co-regulatory proteins modulate these two pathways. We show here a novel role of cyclin D1 as a T3-independent co-repressor for TRs. Cyclin D1 interacted with TR in vitro and in cells in a ligand-independent manner. Cyclin D1 acted to repress both the silencing activity of the unliganded TR and the transcriptional activity of the liganded TR. The repression was not due to the inhibition of the binding of TR to the thyroid hormone response element but by serving as a ligand-independent bridging factor to selectively recruit HDAC3 to form ternary complexes. The repression was augmented by increasing expression of HDAC3 but not by HDAC1 and was alleviated by trichostatin A. Thus, cyclin D1 is a novel ligand-independent co-repressor that opens a new paradigm to understand the molecular basis of the silencing action of TR.
Lin
Huei-Min
HM
Gene Regulation Section, Laboratory of Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Zhao
Li
L
Cheng
Sheue-Yann
SY
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism*; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008024:Ligands; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D000099186:Histone Deacetylase 3
D019938:Cyclin D1; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D008024:Ligands; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D000099186:Histone Deacetylase 3; C012589:trichostatin A