PMID- 34791100
OWN - NLM
STAT- MEDLINE
DCOM- 20211227
LR  - 20230520
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 163
IP  - 1
DP  - 2022 Jan 1
TI  - Regulation of AKT Signaling in Mouse Uterus.
LID - 10.1210/endocr/bqab233 [doi]
LID - bqab233
AB  - 17beta-estradiol (E2) treatment of ovariectomized adult mice stimulates the uterine 
      PI3K-AKT signaling pathway and epithelial proliferation through estrogen receptor 
      1 (ESR1). However, epithelial proliferation occurs independently of E2/ESR1 
      signaling in neonatal uteri. Similarly, estrogen-independent uterine epithelial 
      proliferation is seen in adulthood in mice lacking Ezh2, critical for histone 
      methylation, and in wild-type (WT) mice treated neonatally with estrogen. The 
      role of AKT in estrogen-independent uterine epithelial proliferation was the 
      focus of this study. Expression of the catalytically active phosphorylated form 
      of AKT (p-AKT) and epithelial proliferation were high in estrogen receptor 1 
      knockout and WT mice at postnatal day 6, when E2 concentrations were low, 
      indicating that neither ESR1 nor E2 are essential for p-AKT expression and 
      epithelial proliferation in these mice. However, p-AKT levels and proliferation 
      remained estrogen responsive in preweaning WT mice. Expression of p-AKT and 
      proliferation were both high in uterine luminal epithelium of mice estrogenized 
      neonatally and ovariectomized during adulthood. Increased expression of 
      phosphorylated (inactive) EZH2 was also observed. Consistent with this, Ezh2 
      conditional knockout mice show ovary-independent uterine epithelial proliferation 
      and high epithelial p-AKT. Thus, adult p-AKT expression is constitutive and 
      E2/ESR1 independent in both model systems. Finally, E2-induced p-AKT expression 
      and normal uterine proliferation did not occur in mice lacking membrane (m)ESR1, 
      indicating a key role for membrane ESR1 in AKT activation. These findings 
      emphasize the importance of AKT activation in promoting uterine epithelial 
      proliferation even when that proliferation is not E2/ESR1 dependent and further 
      indicate that p-AKT can be uncoupled from E2/ESR1 signaling in several 
      experimental scenarios.
CI  - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the 
      Endocrine Society. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Sirohi, Vijay K
AU  - Sirohi VK
AD  - Department of Physiological Sciences, University of Florida, Gainesville, FL, 
      USA.
FAU - Medrano, Theresa I
AU  - Medrano TI
AD  - Department of Physiological Sciences, University of Florida, Gainesville, FL, 
      USA.
FAU - Mesa, Ana M
AU  - Mesa AM
AD  - Department of Physiological Sciences, University of Florida, Gainesville, FL, 
      USA.
FAU - Kannan, Athilakshmi
AU  - Kannan A
AD  - Department of Comparative Biosciences, University of Illinois at 
      Urbana-Champaign, Urbana, IL, USA.
FAU - Bagchi, Indrani C
AU  - Bagchi IC
AUID- ORCID: 0000-0001-6032-2632
AD  - Department of Comparative Biosciences, University of Illinois at 
      Urbana-Champaign, Urbana, IL, USA.
FAU - Cooke, Paul S
AU  - Cooke PS
AUID- ORCID: 0000-0002-9370-4896
AD  - Department of Physiological Sciences, University of Florida, Gainesville, FL, 
      USA.
LA  - eng
GR  - R21 HD088006/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Estrogens)
RN  - 0 (Histones)
RN  - EC 2.7.11.1 (Akt1 protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
CIN - Endocrinology. 2022 Mar 1;163(3):. PMID: 35041749
MH  - Animals
MH  - Animals, Newborn
MH  - Catalysis
MH  - Cell Proliferation
MH  - Epithelium/metabolism
MH  - Estrogens/metabolism
MH  - Female
MH  - Genotype
MH  - Histones/metabolism
MH  - Male
MH  - Methylation
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/*biosynthesis/metabolism
MH  - *Signal Transduction
MH  - Uterus/*metabolism
MH  - Wortmannin/pharmacology
PMC - PMC8667855
OTO - NOTNLM
OT  - cell proliferation
OT  - estrogen
OT  - estrogen receptor 1
OT  - membrane steroid receptors
OT  - protein kinase
OT  - uterine epithelium
EDAT- 2021/11/19 06:00
MHDA- 2021/12/28 06:00
PMCR- 2022/11/17
CRDT- 2021/11/18 07:17
PHST- 2021/08/30 00:00 [received]
PHST- 2021/11/19 06:00 [pubmed]
PHST- 2021/12/28 06:00 [medline]
PHST- 2021/11/18 07:17 [entrez]
PHST- 2022/11/17 00:00 [pmc-release]
AID - 6430242 [pii]
AID - bqab233 [pii]
AID - 10.1210/endocr/bqab233 [doi]
PST - ppublish
SO  - Endocrinology. 2022 Jan 1;163(1):bqab233. doi: 10.1210/endocr/bqab233.