| First Author | Fozzatti L | Year | 2011 |
| Journal | Proc Natl Acad Sci U S A | Volume | 108 |
| Issue | 42 | Pages | 17462-7 |
| PubMed ID | 21987803 | Mgi Jnum | J:177419 |
| Mgi Id | MGI:5295088 | Doi | 10.1073/pnas.1107474108 |
| Citation | Fozzatti L, et al. (2011) Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1). Proc Natl Acad Sci U S A 108(42):17462-7 |
| abstractText | Mutations in the ligand-binding domain of the thyroid hormone receptor beta (TRbeta) lead to resistance to thyroid hormone (RTH). These TRbeta 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 TRbeta 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 TRbeta mutant (PV) with mice expressing a mutant Ncor1 allele (Ncor1(DeltaID) mice) that cannot recruit a TR or a PV mutant. Remarkably, in the presence of NCOR1DeltaID, 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 NCOR1DeltaID. Taken together, these data suggest that the aberrant recruitment of NCOR1 by RTH TRbeta 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. |
