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Insulin receptor substrate (IRS)‐1 regulates murine embryonic stem (mES) cells self‐renewal
Author(s) -
Rubin Raphael,
Arzumanyan Alla,
Soliera Angela Rachele,
Ross Brian,
Peruzzi Francesca,
Prisco Marco
Publication year - 2007
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21185
Subject(s) - microbiology and biotechnology , leukemia inhibitory factor , embryonic stem cell , biology , phosphorylation , cellular differentiation , signal transduction , stem cell , gsk 3 , induced pluripotent stem cell , pi3k/akt/mtor pathway , protein kinase b , chemistry , biochemistry , gene
Mouse embryonic stem (mES) cells are pluripotent cells that can be propagated in vitro with leukemia inhibitory factor (LIF) and serum. Intracellular signaling by LIF is principally mediated by activation of STAT‐3, although additional pathways for self‐renewal have been described. Here, we identified a novel role for Insulin receptor substrate‐1 (IRS‐1) as a critical factor in mES cells self‐renewal and differentiation. IRS‐1 is expressed and tyrosyl phosphorylated during mES cells self‐renewal. Differentiation of mES cells, by LIF withdrawal, is associated with a marked reduction in IRS‐1 expression. Targeting of IRS‐1 by si‐IRS‐1 results in a severe reduction of Oct‐4 protein expression and alkaline phosphatase activity, markers of undifferentiated mES cells. IRS‐1 targeting does not interfere with LIF‐induced STAT‐3 phosphorylation, but negatively affects protein kinase B (PKB/AKT) and glycogen synthase kinase‐3 (GSK‐3β) phosphorylation, which are downstream effectors of the LIF‐mediated PI3K signaling cascade. Targeting of IRS‐1 also results in a marked down regulation of Id‐1 and Id‐2 proteins expression, which are important components for self‐renewal of ES cells. Conversely, over expression of IRS‐1 inhibits mES cell differentiation. Taken together, these results suggest that expression and activity of IRS‐1 are critical to the maintenance of the self‐renewal program in mES cells. J. Cell. Physiol. 213: 445–453, 2007. © 2007 Wiley‐Liss, Inc.