PMID- 19589861
OWN - NLM
STAT- MEDLINE
DCOM- 20091022
LR  - 20211203
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Linking)
VI  - 150
IP  - 10
DP  - 2009 Oct
TI  - Mammalian target of rapamycin is activated in association with myometrial 
      proliferation during pregnancy.
PG  - 4672-80
LID - 10.1210/en.2009-0419 [doi]
AB  - The adaptive growth of the uterus during gestation involves gradual changes in 
      cellular phenotypes from the early proliferative to the intermediate synthetic 
      phase of cellular hypertrophy, ending in the final contractile/labour phenotype. 
      The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth 
      and proliferation in many tissues. We hypothesized that mTOR was a mediator of 
      hormone-initiated myometrial hyperplasia during gestation. The protein expression 
      and phosphorylation levels of mTOR, its upstream regulators [insulin receptor 
      substrate-1, phosphoinositide-3-kinase (PI3K), Akt], and downstream effectors 
      [S6-kinase-1 (S6K1) and eI4FE-binding protein 1 (4EBP1)] were analyzed throughout 
      normal pregnancy in rats. In addition, we used an ovariectomized (OVX) rat model 
      to analyze the modulation of the mTOR pathway and proliferative activity of the 
      uterine myocytes by estradiol alone and in combination with the mTOR-specific 
      inhibitor rapamycin. Our results demonstrate that insulin receptor substrate-1 
      protein levels and the phosphorylated (activated) forms of PI3K, mTOR, and S6K1 
      were significantly up-regulated in the rat myometrium during the proliferative 
      phase of pregnancy. Treatment of the OVX rats with estradiol caused a transient 
      increase in IGF-I followed by an up-regulation of the PI3K/mTOR pathway, which 
      became apparent by a cascade of phosphorylation reactions (P-P85, P-Akt, P-mTOR, 
      P-S6K1, and P-4EBP1). Rapamycin blocked activation of P-mTOR, P-S6K1, and P-4EBP1 
      proteins and significantly reduced the number of proliferating cells in the 
      myometrium of OVX rats. Our in vivo data demonstrate that estradiol was able to 
      activate the PI3K/mTOR signaling pathway in uterine myocytes and suggest that 
      this activation is responsible for the induction of myometrial hyperplasia during 
      early gestation.
FAU - Jaffer, Shabana
AU  - Jaffer S
AD  - Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, 
      Canada.
FAU - Shynlova, Oksana
AU  - Shynlova O
FAU - Lye, Stephen
AU  - Lye S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090709
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Carrier Proteins)
RN  - 0 (Eif4ebp1 protein, rat)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Irs1 protein, rat)
RN  - 0 (Phosphoproteins)
RN  - 4TI98Z838E (Estradiol)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (Rps6kb1 protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/metabolism
MH  - *Cell Proliferation
MH  - Enzyme Activation
MH  - Estradiol/*metabolism
MH  - Female
MH  - Gene Expression
MH  - Insulin Receptor Substrate Proteins/metabolism
MH  - Insulin-Like Growth Factor I/genetics/metabolism
MH  - Intracellular Signaling Peptides and Proteins
MH  - Myocytes, Smooth Muscle/physiology
MH  - Myometrium/*growth & development/metabolism
MH  - Ovariectomy
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoproteins/metabolism
MH  - Pregnancy/*physiology
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Signal Transduction
MH  - Sirolimus
MH  - TOR Serine-Threonine Kinases
EDAT- 2009/07/11 09:00
MHDA- 2009/10/23 06:00
CRDT- 2009/07/11 09:00
PHST- 2009/07/11 09:00 [entrez]
PHST- 2009/07/11 09:00 [pubmed]
PHST- 2009/10/23 06:00 [medline]
AID - en.2009-0419 [pii]
AID - 10.1210/en.2009-0419 [doi]
PST - ppublish
SO  - Endocrinology. 2009 Oct;150(10):4672-80. doi: 10.1210/en.2009-0419. Epub 2009 Jul 
      9.