An LXXLL motif in nuclear receptor corepressor mediates ligand-induced repression of the thyroid stimulating hormone-β gene

Nuclear receptor corepressor (N-CoR) regulates gene expression through interaction with DNA-bound nuclear receptors, recruiting multicomponent repressor complexes to the sites of target genes. We recently reported the presence of an LXXLL motif in N-CoR, and showed that this motif interacts in vitro and in vivo with retinoic acid receptor α (RARα) and thyroid hormone receptor β (TRβ). Transient transfection experiments now suggest that TRβ and N-CoR act synergistically and may both be required for ligand-induced repression from the negative TR response element in the thyroid stimulating hormone-β (TSHβ) gene promoter. Mutation of the LXXLL motif in N-CoR abolished ligand-induced repression at this response element. Furthermore, in vitro binding of N-CoR to a complex between TRβ and the negative TR response element was strictly ligand-dependent. We conclude that N-CoR and TRβ cooperate in the regulation of the TSHβ gene and that the ligand-dependent repression is mediated by the LXXLL motif in N-CoR.