PMID- 25733860
OWN - NLM
STAT- MEDLINE
DCOM- 20150604
LR  - 20240221
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 112
IP  - 11
DP  - 2015 Mar 17
TI  - Activation of protein synthesis in mouse uterine epithelial cells by 
      estradiol-17beta is mediated by a PKC-ERK1/2-mTOR signaling pathway.
PG  - E1382-91
LID - 10.1073/pnas.1418973112 [doi]
AB  - The uterine epithelium of mice and humans undergoes cyclical waves of cell 
      proliferation and differentiation under the regulation of estradiol-17beta (E2) and 
      progesterone (P4). These epithelial cells respond to E2 with increased protein 
      and DNA synthesis, whereas P4 inhibits only the E2-induced DNA synthetic 
      response. Here we show that E2 regulates protein synthesis in these epithelial 
      cells through activating PKC that in turn stimulates ERK1/2 to phosphorylate and 
      thereby activate the central regulator of protein synthesis mechanistic target of 
      rapamycin (mTOR). This mTOR pathway is not inhibited by P4. Inhibitor studies 
      with an estrogen receptor (ESR1) antagonist showed the dependence of this mTOR 
      pathway on ESR1 but that once activated, a phosphorylation cascade independent of 
      ESR1 propagates the pathway. E2 also stimulates an IGF1 receptor (IGF1R) to PI3 
      kinase to AKT to GSK-3beta pathway required for activation of the canonical cell 
      cycle machinery that is inhibited by P4. PKC activation did not stimulate this 
      pathway nor does inhibition of PKC or ERK1/2 affect it. These studies therefore 
      indicate a mechanism whereby DNA and protein synthesis are regulated by two 
      ESR1-activated pathways that run in parallel with only the one responsible for 
      the initiation of DNA synthesis blocked by P4. Inhibition of mTOR by rapamycin in 
      vivo resulted in inhibition of E2-induced protein and DNA synthesis. 
      Proliferative diseases of the endometrium such as endometriosis and cancer are 
      common and E2 dependent. Thus, defining this mTOR pathway suggests that local 
      (intrauterine or peritoneal) rapamycin administration might be a therapeutic 
      option for these diseases.
FAU - Wang, Yuxiang
AU  - Wang Y
AD  - Center for the Study of Reproductive Biology and Women's Health, Departments of 
      Developmental and Molecular Biology and.
FAU - Zhu, Liyin
AU  - Zhu L
AD  - Center for the Study of Reproductive Biology and Women's Health, Departments of 
      Developmental and Molecular Biology and.
FAU - Kuokkanen, Satu
AU  - Kuokkanen S
AD  - Center for the Study of Reproductive Biology and Women's Health, Obstetrics and 
      Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY 
      10461; and.
FAU - Pollard, Jeffrey W
AU  - Pollard JW
AD  - Center for the Study of Reproductive Biology and Women's Health, Departments of 
      Developmental and Molecular Biology and Obstetrics and Gynecology and Women's 
      Health, Albert Einstein College of Medicine, Bronx, NY 10461; and Medical 
      Research Council Centre for Reproductive Health, University of Edinburgh, 
      Edinburgh EH16 4TJ, United Kingdom jeff.pollard@ed.ac.uk.
LA  - eng
GR  - G1002033/MRC_/Medical Research Council/United Kingdom
GR  - MR/K015710/1/MRC_/Medical Research Council/United Kingdom
GR  - P30 CA013330/CA/NCI NIH HHS/United States
GR  - U54 HD058155/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150302
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 (Estrogen Receptor alpha)
RN  - 4G7DS2Q64Y (Progesterone)
RN  - 4TI98Z838E (Estradiol)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Enzyme Activation/drug effects
MH  - Epithelial Cells/*metabolism
MH  - Estradiol/*pharmacology
MH  - Estrogen Receptor alpha/metabolism
MH  - Female
MH  - Humans
MH  - MAP Kinase Signaling System/*drug effects
MH  - Mice
MH  - Models, Biological
MH  - Progesterone/pharmacology
MH  - Protein Biosynthesis/*drug effects
MH  - Protein Kinase C/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Uterus/*cytology
PMC - PMC4371960
OTO - NOTNLM
OT  - DNA synthesis
OT  - estrogen
OT  - mTOR
OT  - protein kinase C
OT  - protein synthesis
COIS- The authors declare no conflict of interest.
EDAT- 2015/03/04 06:00
MHDA- 2015/06/05 06:00
PMCR- 2015/09/17
CRDT- 2015/03/04 06:00
PHST- 2015/03/04 06:00 [entrez]
PHST- 2015/03/04 06:00 [pubmed]
PHST- 2015/06/05 06:00 [medline]
PHST- 2015/09/17 00:00 [pmc-release]
AID - 1418973112 [pii]
AID - 201418973 [pii]
AID - 10.1073/pnas.1418973112 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1382-91. doi: 
      10.1073/pnas.1418973112. Epub 2015 Mar 2.