PMID- 17169389
OWN - NLM
STAT- MEDLINE
DCOM- 20070511
LR  - 20191003
IS  - 0039-128X (Print)
IS  - 1878-5867 (Electronic)
IS  - 0039-128X (Linking)
VI  - 72
IP  - 2
DP  - 2007 Feb
TI  - Novel functions of thyroid hormone receptor mutants: beyond nucleus-initiated 
      transcription.
PG  - 171-9
AB  - Study of molecular actions of thyroid hormone receptor beta (TRbeta) mutants in 
      vivo has been facilitated by creation of a mouse model (TRbetaPV mouse) that 
      harbors a knockin mutant of TRbeta (denoted PV). PV, which was identified in a 
      patient with resistance to thyroid hormone, has lost T3 binding activity and 
      transcription capacity. The striking phenotype of thyroid cancer exhibited by 
      TRbeta(PV/PV) mice has allowed the elucidation of novel oncogenic activity of a 
      TRbeta mutant (PV) [PAS1] beyond nucleus-initiated transcription. PV was found to 
      physically interact with the regulatory p85alpha subunit of phosphatidylinositol 
      3-kinase (PI3K) in both the nuclear and cytoplasmic compartments. This 
      protein-protein interaction activates the PI3K signaling by increasing 
      phosphorylation of AKT, mammalian target of rapamycin (mTOR), and p70(S6K). PV, 
      via interaction with p85alpha, also activates the PI3K-integrin-linked 
      kinase-matrix metalloproteinase-2 signaling pathway in the extra-nuclear 
      compartment. The PV-mediated PI3K activation results in increased cell 
      proliferation, motility, migration, and metastasis. In addition to affecting 
      these membrane-initiated signaling events, PV affects the stability of the 
      pituitary tumor-transforming gene (PTTG) product. PTTG (also known as securin), a 
      critical mitotic checkpoint protein, is physically associated with TRbeta or PV 
      in vivo. Concomitant with T3-induced degradation of TRbeta, PTTG is degraded by 
      the proteasome machinery, but no such degradation occurs when PTTG is associated 
      with PV. The degradation of PTTG/TRbeta is activated by the direct interaction of 
      the T3-bound TRbeta with the steroid receptor coactivator-3 (SRC-3) that recruits 
      a proteasome activator (PA28gamma). PV that does not bind T3 cannot interact 
      directly with SRC-3/PA28gamma to activate proteasome degradation, and the absence 
      of degradation results in an aberrant accumulation of PTTG. The PV-induced 
      failure of timely degradation of PTTG results in mitotic abnormalities. PV, via 
      novel protein-protein interaction and transcription regulation, acts to 
      antagonize the functions of wild-type TRs and contributes to the oncogenic 
      functions of this mutation.
FAU - Furuya, Fumihiko
AU  - Furuya F
AD  - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
FAU - Ying, Hao
AU  - Ying H
FAU - Zhao, Li
AU  - Zhao L
FAU - Cheng, Sheue-yann
AU  - Cheng SY
LA  - eng
GR  - ZIA BC011191-01/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Review
DEP - 20061213
PL  - United States
TA  - Steroids
JT  - Steroids
JID - 0404536
RN  - 0 (Receptors, Thyroid Hormone)
SB  - IM
MH  - Animals
MH  - Cell Nucleus/*physiology
MH  - Humans
MH  - *Mutation
MH  - Receptors, Thyroid Hormone/genetics/*physiology
MH  - Transcription, Genetic/*physiology
PMC - PMC2794798
MID - NIHMS19590
EDAT- 2006/12/16 09:00
MHDA- 2007/05/12 09:00
PMCR- 2009/12/16
CRDT- 2006/12/16 09:00
PHST- 2006/10/06 00:00 [received]
PHST- 2006/11/11 00:00 [accepted]
PHST- 2006/12/16 09:00 [pubmed]
PHST- 2007/05/12 09:00 [medline]
PHST- 2006/12/16 09:00 [entrez]
PHST- 2009/12/16 00:00 [pmc-release]
AID - S0039-128X(06)00243-1 [pii]
AID - 10.1016/j.steroids.2006.11.005 [doi]
PST - ppublish
SO  - Steroids. 2007 Feb;72(2):171-9. doi: 10.1016/j.steroids.2006.11.005. Epub 2006 
      Dec 13.