PMID- 20484410
OWN - NLM
STAT- MEDLINE
DCOM- 20100923
LR  - 20211203
IS  - 1944-9917 (Electronic)
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 24
IP  - 7
DP  - 2010 Jul
TI  - cAMP-dependent activation of mammalian target of rapamycin (mTOR) in thyroid 
      cells. Implication in mitogenesis and activation of CDK4.
PG  - 1453-68
LID - 10.1210/me.2010-0087 [doi]
AB  - How cAMP-dependent protein kinases [protein kinase A (PKA)] transduce the 
      mitogenic stimulus elicited by TSH in thyroid cells to late activation of cyclin 
      D3-cyclin-dependent kinase 4 (CDK4) remains enigmatic. Here we show in PC Cl3 rat 
      thyroid cells that TSH/cAMP, like insulin, activates the mammalian target of 
      rapamycin (mTOR)-raptor complex (mTORC1) leading to phosphorylation of S6K1 and 
      4E-BP1. mTORC1-dependent S6K1 phosphorylation in response to both insulin and 
      cAMP required amino acids, whereas inhibition of AMP-activated protein kinase and 
      glycogen synthase kinase 3 enhanced insulin but not cAMP effects. Unlike insulin, 
      TSH/cAMP did not activate protein kinase B or induce tuberous sclerosis complex 2 
      phosphorylation at T1462 and Y1571. However, like insulin, TSH/cAMP produced a 
      stable increase in mTORC1 kinase activity that was associated with augmented 
      4E-BP1 binding to raptor. This could be caused in part by T246 phosphorylation of 
      PRAS40, which was found as an in vitro substrate of PKA. Both in PC Cl3 cells and 
      primary dog thyrocytes, rapamycin inhibited DNA synthesis and retinoblastoma 
      protein phosphorylation induced by TSH and insulin. Although rapamycin reduced 
      cyclin D3 accumulation, the abundance of cyclin D3-CDK4 complexes was not 
      affected. However, rapamycin inhibited the activity of these complexes by 
      decreasing the TSH and insulin-mediated stimulation of activating T172 
      phosphorylation of CDK4. We propose that mTORC1 activation by TSH, at least in 
      part through PKA-dependent phosphorylation of PRAS40, crucially contributes to 
      mediate cAMP-dependent mitogenesis by regulating CDK4 T172-phosphorylation.
FAU - Blancquaert, Sara
AU  - Blancquaert S
AD  - Institute of Interdisciplinary Research, Universite Libre de Bruxelles, Campus 
      Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium.
FAU - Wang, Lifu
AU  - Wang L
FAU - Paternot, Sabine
AU  - Paternot S
FAU - Coulonval, Katia
AU  - Coulonval K
FAU - Dumont, Jacques E
AU  - Dumont JE
FAU - Harris, Thurl E
AU  - Harris TE
FAU - Roger, Pierre P
AU  - Roger PP
LA  - eng
GR  - R01 DK028312/DK/NIDDK NIH HHS/United States
GR  - R01 DK052753/DK/NIDDK NIH HHS/United States
GR  - DK28312/DK/NIDDK NIH HHS/United States
GR  - DK52753/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100519
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Cyclin D3)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 9002-71-5 (Thyrotropin)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Cyclic AMP/*pharmacology
MH  - Cyclin D3/metabolism
MH  - Cyclin-Dependent Kinase 4/*metabolism
MH  - Dogs
MH  - Electrophoresis, Gel, Two-Dimensional
MH  - Immunoprecipitation
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Binding
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Rats
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Thyroid Gland/cytology/*metabolism
MH  - Thyrotropin/pharmacology
PMC - PMC2903905
EDAT- 2010/05/21 06:00
MHDA- 2010/09/24 06:00
PMCR- 2011/07/01
CRDT- 2010/05/21 06:00
PHST- 2010/05/21 06:00 [entrez]
PHST- 2010/05/21 06:00 [pubmed]
PHST- 2010/09/24 06:00 [medline]
PHST- 2011/07/01 00:00 [pmc-release]
AID - me.2010-0087 [pii]
AID - 4671 [pii]
AID - 10.1210/me.2010-0087 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2010 Jul;24(7):1453-68. doi: 10.1210/me.2010-0087. Epub 2010 May 
      19.