PMID- 24550004 OWN - NLM STAT- MEDLINE DCOM- 20140603 LR - 20211021 IS - 1098-5549 (Electronic) IS - 0270-7306 (Print) IS - 0270-7306 (Linking) VI - 34 IP - 9 DP - 2014 May TI - Thyroid hormone signaling in vivo requires a balance between coactivators and corepressors. PG - 1564-75 LID - 10.1128/MCB.00129-14 [doi] AB - 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. FAU - Vella, Kristen R AU - Vella KR AD - Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. FAU - Ramadoss, Preeti AU - Ramadoss P FAU - Costa-E-Sousa, Ricardo H AU - Costa-E-Sousa RH FAU - Astapova, Inna AU - Astapova I FAU - Ye, Felix D AU - Ye FD FAU - Holtz, Kaila A AU - Holtz KA FAU - Harris, Jamie C AU - Harris JC FAU - Hollenberg, Anthony N AU - Hollenberg AN LA - eng GR - R56 DK056123/DK/NIDDK NIH HHS/United States GR - DK091403/DK/NIDDK NIH HHS/United States GR - T32 DK007516/DK/NIDDK NIH HHS/United States GR - R01 DK056123/DK/NIDDK NIH HHS/United States GR - T3207516/PHS HHS/United States GR - K01 DK091403/DK/NIDDK NIH HHS/United States GR - R01 DK078090/DK/NIDDK NIH HHS/United States GR - DK078090/DK/NIDDK NIH HHS/United States GR - DK056123/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140218 PL - United States TA - Mol Cell Biol JT - Molecular and cellular biology JID - 8109087 RN - 0 (Co-Repressor Proteins) RN - 0 (Nuclear Receptor Coactivator 2) RN - 0 (Thyroid Hormone Receptors beta) RN - 0 (Thyroid Hormones) RN - 06LU7C9H1V (Triiodothyronine) RN - 9002-71-5 (Thyrotropin) RN - EC 2.3.1.48 (Nuclear Receptor Coactivator 1) SB - IM MH - Animals MH - Co-Repressor Proteins/*metabolism MH - Female MH - Gene Deletion MH - Humans MH - Male MH - Mice MH - Mutation MH - Nuclear Receptor Coactivator 1/genetics/*metabolism MH - Nuclear Receptor Coactivator 2/*metabolism MH - Pituitary Gland/metabolism MH - *Signal Transduction MH - Thyroid Hormone Receptors beta/genetics/metabolism MH - Thyroid Hormone Resistance Syndrome/blood/genetics/*metabolism MH - Thyroid Hormones/blood/*metabolism MH - Thyrotropin/blood/metabolism MH - Triiodothyronine/metabolism PMC - PMC3993596 EDAT- 2014/02/20 06:00 MHDA- 2014/06/04 06:00 PMCR- 2014/11/01 CRDT- 2014/02/20 06:00 PHST- 2014/02/20 06:00 [entrez] PHST- 2014/02/20 06:00 [pubmed] PHST- 2014/06/04 06:00 [medline] PHST- 2014/11/01 00:00 [pmc-release] AID - MCB.00129-14 [pii] AID - 00129-14 [pii] AID - 10.1128/MCB.00129-14 [doi] PST - ppublish SO - Mol Cell Biol. 2014 May;34(9):1564-75. doi: 10.1128/MCB.00129-14. Epub 2014 Feb 18.