title: Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1).
abstract: Mutations in the ligand-binding domain of the thyroid hormone receptor β (TRβ) lead to resistance to thyroid hormone (RTH). These TRβ mutants function in a dominant-negative fashion to interfere with the transcription activity of wild-type thyroid hormone receptors (TRs), leading to dysregulation of the pituitary-thyroid axis and resistance in peripheral tissues. The molecular mechanism by which TRβ mutants cause RTH has been postulated to be an inability of the mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone (TH)-mediated transcription activity. To test this hypothesis in vivo, we crossed Thrb(PV) mice (a model of RTH) expressing a human TRβ mutant (PV) with mice expressing a mutant Ncor1 allele (Ncor1(ΔID) mice) that cannot recruit a TR or a PV mutant. Remarkably, in the presence of NCOR1ΔID, the abnormally elevated thyroid-stimulating hormone and TH levels found in Thrb(PV) mice were modestly but significantly corrected. Furthermore, thyroid hyperplasia, weight loss, and other hallmarks of RTH were also partially reverted in mice expressing NCOR1ΔID. Taken together, these data suggest that the aberrant recruitment of NCOR1 by RTH TRβ mutants leads to clinical RTH in humans. The present study suggests that therapies aimed at the TR-NCOR1 interaction or its downstream actions could be tested as potential targets in treating RTH.
authors: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Laura
authors: L
authors: Fozzatti
authors: Changxue
authors: C
authors: Lu
authors: Dong Wook
authors: DW
authors: Kim
authors: Jeong Won
authors: JW
authors: Park
authors: Inna
authors: I
authors: Astapova
authors: Oksana
authors: O
authors: Gavrilova
authors: Mark C
authors: MC
authors: Willingham
authors: Anthony N
authors: AN
authors: Hollenberg
authors: Sheue-yann
authors: SY
authors: Cheng
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018776:Genes, erbA; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D056971:Nuclear Receptor Co-Repressor 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000502:physiology; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D013963:Thyroid Hormones / Q000097:blood / Q000502:physiology
chemical_list: C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones