An LXXLL motif in nuclear receptor corepressor mediates ligand-induced repression of the thyroid stimulating hormone-beta 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 alpha (RARalpha) and thyroid hormone receptor beta (TRbeta). Transient transfection experiments now suggest that TRbeta 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-beta (TSHbeta) 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 TRbeta and the negative TR response element was strictly ligand-dependent. We conclude that N-CoR and TRbeta cooperate in the regulation of the TSHbeta gene and that the ligand-dependent repression is mediated by the LXXLL motif in N-CoR.