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2016 ; 7
(1
): e2050
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Leukemia inhibitory factor (LIF) withdrawal activates mTOR signaling pathway in
mouse embryonic stem cells through the MEK/ERK/TSC2 pathway
#MMPMID26775702
Cherepkova MY
; Sineva GS
; Pospelov VA
Cell Death Dis
2016[Jan]; 7
(1
): e2050
PMID26775702
show ga
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withdrawn from culture medium, the mTOR activity rapidly increases as detected by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
by an augmentation of fgf5 gene expression - a marker of post-implantation
epiblast. Together, these data indicate that LIF-depleted mouse ESCs undergo a
transition from the LIF/STAT3-supported pluripotent state to the
FGFR/ERK-committed primed-like state with expression of early differentiation
markers mediated through activation of mTOR signaling.