Leukemia inhibitory factor (LIF) withdrawal activates mTOR signaling pathway in mouse embryonic stem cells through the MEK/ERK/TSC2 pathway

Cell Death & Disease
M Y CherepkovaV A Pospelov

Abstract

Leukemia inhibitory factor (LIF) is indispensable to maintain the pluripotent state of mouse embryonic stem cells (ESCs), but the mechanisms underlying the role of LIF/STAT3 pathway are yet poorly understood. Here we first showed that the LIF/STAT3-regulated signaling pathway contributes to the maintenance of self-renewal and pluripotency of mouse ESCs by suppressing mTOR (mammalian target of rapamycin), which is necessary for early differentiation. When LIF is withdrawn from culture medium, the mTOR activity rapidly increases as detected by phosphorylation of its targets - ribosomal protein S6 and translation factor 4EBP1. In turn, suppression of STAT3 phosphorylation on Tyr-705 by a specific small molecule WP1066 also activates phosphorylation of the mTOR target S6 ribosomal protein. LIF removal strongly activates ERK activity indicating that ERK can be involved in either direct phosphorylation of mTOR or phosphorylation of an upstream negative regulator of mTOR - TSC1/TSC2 proteins. According to western blotting data, LIF withdrawal leads to phosphorylation of TSC2 protein thereby relieving its negative effect on mTOR activity. mTOR activation is accompanied by a decrease of pluripotent gene expression Oct-4, Nanog, Sox2 and...Continue Reading

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Citations

Feb 24, 2017·Journal of Cellular Biochemistry·Na LiJinlian Hua
Aug 22, 2017·Asian-Australasian Journal of Animal Sciences·Azra MemonWoon Kyu Lee
Mar 15, 2019·Current Stem Cell Research & Therapy·Maryam FarzanehSeyed Esmaeil Khoshnam
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Jul 28, 2016·Biology Direct·Sofia Gkountela, Nicola Aceto
Feb 8, 2019·Cell Death Discovery·Irina I SuvorovaValery A Pospelov
May 16, 2020·Drug Delivery and Translational Research·Nilesh RaiVibhav Gautam
Mar 31, 2019·Nature Communications·Charlène NiogretGreta Guarda
Mar 7, 2020·Frontiers in Cell and Developmental Biology·Majid Mossahebi-MohammadiXiaokun Li
Sep 26, 2020·Cell & Bioscience·Qian SongBosheng Zhao
Oct 28, 2019·Frontiers in Endocrinology·Zaixin Guo, Qi Yu
Oct 15, 2018·Molecular Metabolism·Manoj K GuptaRohit N Kulkarni
Apr 19, 2021·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Wenlong WangHideko Sone

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Methods Mentioned

BETA
flow cytometry
transfection
PCR

Software Mentioned

pro Analyzer
Gel
MODFIT LT

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