Insulin receptor substrate (IRS)‐1 regulates murine embryonic stem (mES) cells self‐renewal

Abstract

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-3b) 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.

MicroRNAs in breast cancer: oncogene and tumor suppressors with clinical potential

“…Insulin receptor substrate-1 (IRS-1), which is necessary for BT-IC differentiation, has been shown to be a direct target of miR-145 (Rubin et al, 2007). ER-α is reported to be negatively regulated by miR-145 at two complementary sites, thereby mediating breast cancer cell growth (Spizzo et al, 2010).…”

Insulin receptor and cancer

“…Interestingly, cord levels of IGFs in the newborn are positively associated with the total number of stem cells and with future cancer risk (Savarese et al 2007). In mouse ES cells, the IR/IGF1R substrate IRS1 is a critical component of the self-renewing program (Rubin et al 2007).…”

microRNA, Cell Cycle, and Human Breast Cancer

“…Shi et al 6 showed that miR-145 inhibits human cancer cell growth in vitro via the 3ЈUTR of the type 1 insulin-like growth factor receptor and its docking protein, the insulin receptor substrate-1 (IRS-1). Rubin et al 80 found IRS-1 was highly expressed in undifferentiated murine embryonic stem cells (mESC), with decreased expression when the cells differentiated. Forced expression of IRS-1 inhibited mESC differentiation suggesting miR-145 and IRS-1 function in stem cell differentiation.…”