PMID- 21987803
OWN - NLM
STAT- MEDLINE
DCOM- 20111230
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 108
IP  - 42
DP  - 2011 Oct 18
TI  - Resistance to thyroid hormone is modulated in vivo by the nuclear receptor 
      corepressor (NCOR1).
PG  - 17462-7
LID - 10.1073/pnas.1107474108 [doi]
AB  - 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.
FAU - Fozzatti, Laura
AU  - Fozzatti L
AD  - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD 20892, USA.
FAU - Lu, Changxue
AU  - Lu C
FAU - Kim, Dong Wook
AU  - Kim DW
FAU - Park, Jeong Won
AU  - Park JW
FAU - Astapova, Inna
AU  - Astapova I
FAU - Gavrilova, Oksana
AU  - Gavrilova O
FAU - Willingham, Mark C
AU  - Willingham MC
FAU - Hollenberg, Anthony N
AU  - Hollenberg AN
FAU - Cheng, Sheue-yann
AU  - Cheng SY
LA  - eng
GR  - DK-056123/DK/NIDDK NIH HHS/United States
GR  - R56 DK056123/DK/NIDDK NIH HHS/United States
GR  - R01 DK078090/DK/NIDDK NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
GR  - R01 DK056123/DK/NIDDK NIH HHS/United States
GR  - DK-078090/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20111010
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (NCOR1 protein, human)
RN  - 0 (Ncor1 protein, mouse)
RN  - 0 (Nuclear Receptor Co-Repressor 1)
RN  - 0 (Thyroid Hormone Receptors beta)
RN  - 0 (Thyroid Hormones)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Genes, erbA
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Mice, Transgenic
MH  - Mutation
MH  - Nuclear Receptor Co-Repressor 1/chemistry/genetics/*physiology
MH  - Protein Structure, Tertiary
MH  - Sequence Deletion
MH  - Thyroid Hormone Receptors beta/genetics/physiology
MH  - Thyroid Hormone Resistance Syndrome/*genetics/pathology/*physiopathology
MH  - Thyroid Hormones/blood/physiology
PMC - PMC3198316
COIS- The authors declare no conflict of interest.
EDAT- 2011/10/12 06:00
MHDA- 2011/12/31 06:00
PMCR- 2012/04/18
CRDT- 2011/10/12 06:00
PHST- 2011/10/12 06:00 [entrez]
PHST- 2011/10/12 06:00 [pubmed]
PHST- 2011/12/31 06:00 [medline]
PHST- 2012/04/18 00:00 [pmc-release]
AID - 1107474108 [pii]
AID - 201107474 [pii]
AID - 10.1073/pnas.1107474108 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17462-7. doi: 
      10.1073/pnas.1107474108. Epub 2011 Oct 10.