| First Author | Vella KR | Year | 2014 |
| Journal | Mol Cell Biol | Volume | 34 |
| Issue | 9 | Pages | 1564-75 |
| PubMed ID | 24550004 | Mgi Jnum | J:213682 |
| Mgi Id | MGI:5585573 | Doi | 10.1128/MCB.00129-14 |
| Citation | Vella KR, et al. (2014) Thyroid hormone signaling in vivo requires a balance between coactivators and corepressors. Mol Cell Biol 34(9):1564-75 |
| abstractText | Resistance to thyroid hormone (RTH), a human syndrome, is characterized by high thyroid hormone (TH) and thyroid-stimulating hormone (TSH) levels. Mice with mutations in the thyroid hormone receptor beta (TRbeta) gene that cannot bind steroid receptor coactivator 1 (SRC-1) and Src-1(-/-) mice both have phenotypes similar to that of RTH. Conversely, mice expressing a mutant nuclear corepressor 1 (Ncor1) allele that cannot interact with TRbeta, termed NCoRDeltaID, have low TH levels and normal TSH. We hypothesized that Src-1(-/-) mice have RTH due to unopposed corepressor action. To test this, we crossed NCoRDeltaID and Src-1(-/-) mice to create mice deficient for coregulator action in all cell types. Remarkably, NCoR(DeltaID/DeltaID) Src-1(-/-) mice have normal TH and TSH levels and are triiodothryonine (T(3)) sensitive at the level of the pituitary. Although absence of SRC-1 prevented T(3) activation of key hepatic gene targets, NCoR(DeltaID/DeltaID) Src-1(-/-) mice reacquired hepatic T(3) sensitivity. Using in vivo chromatin immunoprecipitation assays (ChIP) for the related coactivator SRC-2, we found enhanced SRC-2 recruitment to TR-binding regions of genes in NCoR(DeltaID/DeltaID) Src-1(-/-) mice, suggesting that SRC-2 is responsible for T(3) sensitivity in the absence of NCoR1 and SRC-1. Thus, T(3) targets require a critical balance between NCoR1 and SRC-1. Furthermore, replacement of NCoR1 with NCoRDeltaID corrects RTH in Src-1(-/-) mice through increased SRC-2 recruitment to T(3) target genes. |
