PMID- 23610395
OWN - NLM
STAT- MEDLINE
DCOM- 20130719
LR  - 20211021
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 19
DP  - 2013 May 7
TI  - Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated 
      thyroid hormone receptor alpha.
PG  - 7850-5
LID - 10.1073/pnas.1222334110 [doi]
AB  - Genetic evidence from patients with mutations of the thyroid hormone receptor alpha 
      gene (THRA) indicates that the dominant negative activity of mutants underlies 
      the pathological manifestations. However, the molecular mechanisms by which TRalpha1 
      mutants exert dominant negative activity in vivo are not clear. We tested the 
      hypothesis that the severe hypothyroidism in patients with THRA mutations is due 
      to an inability of TRalpha1 mutants to properly release the nuclear corepressors 
      (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We 
      crossed Thra1(PV) mice, expressing a dominant negative TRalpha1 mutant (TRalpha1PV), with 
      mice expressing a mutant Ncor1 allele (Ncor1(DeltaID) mice) that cannot recruit the 
      TR or PV mutant. TRalpha1PV shares the same C-terminal mutated sequences as those of 
      patients with frameshift mutations of the THRA gene. Remarkably, NCOR1DeltaID 
      ameliorated abnormalities in the thyroid-pituitary axis of Thra1(PV/+) mice. The 
      severe retarded growth, infertility, and delayed bone development were partially 
      reverted in Thra1(PV/+) mice expressing NCOR1DeltaID. The impaired adipogenesis was 
      partially corrected by de-repression of peroxisome-proliferator activated 
      receptor gamma and CCAAT/enhancer-binding protein alpha gene, due to the inability of 
      TRalpha1PV to recruit NCOR1DeltaID to form a repressor complex. Thus, the aberrant 
      recruitment of NCOR1 by TRalpha1 mutants could lead to clinical hypothyroidism in 
      humans. Therefore, therapies aimed at the TRalpha1-NCOR1 interaction or its 
      downstream actions could be tested as potential targets in treating TRalpha1 
      mutant-mediated hypothyroidism in patients.
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 - Kim, Dong Wook
AU  - Kim DW
FAU - Park, Jeong Won
AU  - Park JW
FAU - Willingham, Mark C
AU  - Willingham MC
FAU - Hollenberg, Anthony N
AU  - Hollenberg AN
FAU - Cheng, Sheue-Yann
AU  - Cheng SY
LA  - eng
GR  - R01 DK056123/DK/NIDDK NIH HHS/United States
GR  - R56 DK056123/DK/NIDDK NIH HHS/United States
GR  - DK056123/DK/NIDDK NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20130422
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, mouse)
RN  - 0 (Nuclear Receptor Co-Repressor 1)
RN  - 0 (Thyroid Hormone Receptors alpha)
RN  - 06LU7C9H1V (Triiodothyronine)
RN  - Q51BO43MG4 (Thyroxine)
SB  - IM
MH  - Alleles
MH  - Animals
MH  - Bone Development
MH  - Crosses, Genetic
MH  - Female
MH  - Frameshift Mutation
MH  - Hypothyroidism/metabolism/physiopathology
MH  - Infertility/pathology
MH  - Lipid Metabolism
MH  - Male
MH  - Mice
MH  - *Mutation
MH  - Nuclear Receptor Co-Repressor 1/*physiology
MH  - Pituitary Gland/metabolism/pathology
MH  - Protein Interaction Domains and Motifs
MH  - Thyroid Gland/metabolism/pathology
MH  - Thyroid Hormone Receptors alpha/*metabolism
MH  - Thyroxine/metabolism
MH  - Triiodothyronine/metabolism
PMC - PMC3651436
OTO - NOTNLM
OT  - fertility defect
OT  - growth retardation
OT  - lipid metabolism
COIS- The authors declare no conflict of interest.
EDAT- 2013/04/24 06:00
MHDA- 2013/07/20 06:00
PMCR- 2013/11/07
CRDT- 2013/04/24 06:00
PHST- 2013/04/24 06:00 [entrez]
PHST- 2013/04/24 06:00 [pubmed]
PHST- 2013/07/20 06:00 [medline]
PHST- 2013/11/07 00:00 [pmc-release]
AID - 1222334110 [pii]
AID - 201222334 [pii]
AID - 10.1073/pnas.1222334110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 May 7;110(19):7850-5. doi: 
      10.1073/pnas.1222334110. Epub 2013 Apr 22.