Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1)

FOZZATTI LAURA; LU CHANGXUE; KIM DONG-WOOK; PARK JEONG WON; ASTAPOVA INNA; GAVRILOVA OKSANA; WILLINGHAM MARK C; HOLLENBERG ANTHONY N; CHENG SHEUE-YANN

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2011 p. 17462 - 17462

Mutations in the ligand-binding domain of the thyroid hormonereceptor β (TRβ) lead to resistance to thyroid hormone (RTH). TheseTRβ mutants function in a dominant-negative fashion to interferewith the transcription activity of wild-type thyroid hormone receptors(TRs), leading to dysregulation of the pituitary-thyroid axisand resistance in peripheral tissues. The molecular mechanism bywhich TRβ mutants cause RTH has been postulated to be an inabilityof the mutants to properly release the nuclear corepressors(NCORs), thereby inhibiting thyroid hormone (TH)-mediated transcriptionactivity. To test this hypothesis in vivo, we crossed ThrbPVmice (a model of RTH) expressing a human TRβ mutant (PV) withmice expressing a mutant Ncor1 allele (Ncor1ΔID mice) that cannotrecruit a TR or a PV mutant. Remarkably, in the presence ofNCOR1ΔID, the abnormally elevated thyroid-stimulating