PMID- 25710488
OWN - NLM
STAT- MEDLINE
DCOM- 20151117
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 2
DP  - 2015
TI  - Promotion of ovarian follicle growth following mTOR activation: synergistic 
      effects of AKT stimulators.
PG  - e0117769
LID - 10.1371/journal.pone.0117769 [doi]
LID - e0117769
AB  - Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and mTOR 
      signaling is important in regulating cell growth and proliferation. Recent 
      studies using oocyte- and granulosa cell-specific deletion of mTOR inhibitor 
      genes TSC1 or TSC2 demonstrated the important role of mTOR signaling in the 
      promotion of ovarian follicle development. We now report that treatment of 
      ovaries from juvenile mice with an mTOR activator MHY1485 stimulated mTOR, S6K1 
      and rpS6 phosphorylation. Culturing ovaries for 4 days with MHY1485 increased 
      ovarian explant weights and follicle development. In vivo studies further 
      demonstrated that pre-incubation of these ovaries with MHY1485 for 2 days, 
      followed by allo-grafting into kidney capsules of adult ovariectomized hosts for 
      5 days, led to marked increases in graft weights and promotion of follicle 
      development. Mature oocytes derived from MHY1485-activated ovarian grafts could 
      be successfully fertilized, leading the delivery of healthy pups. We further 
      treated ovaries with the mTOR activator together with AKT activators (PTEN 
      inhibitor and phosphoinositol-3-kinase stimulator) before grafting and found 
      additive enhancement of follicle growth. Our studies demonstrate the ability of 
      an mTOR activator in promoting follicle growth, leading to a potential strategy 
      to stimulate preantral follicle growth in infertile patients.
FAU - Cheng, Yuan
AU  - Cheng Y
AD  - Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford 
      University School of Medicine, Stanford, CA, United States of America.
FAU - Kim, Jaehong
AU  - Kim J
AD  - Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford 
      University School of Medicine, Stanford, CA, United States of America.
FAU - Li, Xiao Xiao
AU  - Li XX
AD  - Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford 
      University School of Medicine, Stanford, CA, United States of America.
FAU - Hsueh, Aaron J
AU  - Hsueh AJ
AD  - Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford 
      University School of Medicine, Stanford, CA, United States of America.
LA  - eng
GR  - P50 HD068158/HD/NICHD NIH HHS/United States
GR  - U54 HD068158/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150224
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (4,6-dimorpholino-N-(4-nitrophenyl)-1,3,5-triazin-2-amine)
RN  - 0 (Morpholines)
RN  - 0 (Ribosomal Protein S6)
RN  - 0 (Triazines)
RN  - 0 (ribosomal protein S6, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (Rps6ka1 protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (Pten protein, mouse)
SB  - IM
MH  - Animals
MH  - Female
MH  - In Vitro Oocyte Maturation Techniques
MH  - Mice
MH  - Morpholines/pharmacology
MH  - Oocytes/drug effects/metabolism
MH  - Ovarian Follicle/*growth & development
MH  - Ovary/cytology/drug effects/metabolism
MH  - PTEN Phosphohydrolase/antagonists & inhibitors/metabolism
MH  - Phosphatidylinositol 3-Kinases/chemistry/metabolism
MH  - Phosphorylation/drug effects
MH  - Proto-Oncogene Proteins c-akt/agonists/*metabolism
MH  - Ribosomal Protein S6/metabolism
MH  - Ribosomal Protein S6 Kinases, 90-kDa/metabolism
MH  - TOR Serine-Threonine Kinases/chemistry/*metabolism
MH  - Triazines/pharmacology
PMC - PMC4340052
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/02/25 06:00
MHDA- 2015/11/18 06:00
PMCR- 2015/02/24
CRDT- 2015/02/25 06:00
PHST- 2014/10/05 00:00 [received]
PHST- 2015/01/02 00:00 [accepted]
PHST- 2015/02/25 06:00 [entrez]
PHST- 2015/02/25 06:00 [pubmed]
PHST- 2015/11/18 06:00 [medline]
PHST- 2015/02/24 00:00 [pmc-release]
AID - PONE-D-14-44737 [pii]
AID - 10.1371/journal.pone.0117769 [doi]
PST - epublish
SO  - PLoS One. 2015 Feb 24;10(2):e0117769. doi: 10.1371/journal.pone.0117769. 
      eCollection 2015.