Nuclear insulin receptor substrate-1 activates promoters of cell cycle progression genes

Abstract

The insulin receptor substrate-1 (IRS-1) is a docking protein of the insulin-like growth factor-1 (IGF-1) receptor and of the insulin receptor. IRS-1 sends a strong mitogenic, anti-apoptotic signal and plays an important role in cell transformation and cancer. IRS-1 translocates to nuclei of cells, where it increases the activity of the rDNA, c-myc and cyclin D1 promoters. We show, by chromatin immunoprecipitation, occupancy by IRS-1 of the same promoters. Both promoter activation and promoter occupancy are IGF-1-dependent. In cells that respond to IGF-1 but in which IRS-1 does not translocate to nuclei, promoter occupancy is absent and promoter activation is absent or much reduced. Transcriptional activation of c-myc and cyclin D1 promoters by nuclear IRS-1 does not occur with a mutant, inactive IRS-1 protein (deletion of the phosphotyrosine-binding domain, PTB) and does not require PI3-kinase activity. Taken together, these results indicate a novel mechanism by which nuclear IRS-1 activates cell cycle genes.

YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation

“…Since we also detected YAP1 in the nucleus of CGNPs (Fig. 2D), and previous studies have implicated IRS1 in transcriptional regulation of proliferation-associated genes (Wu et al 2008), we asked whether these two proteins interact. When we immunoprecipitated IRS1 from Shh-treated CGNPs, we detected YAP1 by Western blotting (Fig.…”

Wnt signaling regulates mitochondrial physiology and insulin sensitivity

“…An emerging notion, reinforced by our findings here, is that of IRS-1 as a nuclear transcriptional regulator that responds to extracellular signals. IRS-1 has been reported previously to interact with the estrogen receptor a on estrogen-responsive promoters, and to activate IGF-1-responsive promoters (Morelli et al 2004;Wu et al 2008). IRS-1 is known to signal downstream from many classical hormones, including growth hormone, prolactin, and gonadal steroid hormones, as well as various cytokines and growth factors, and it is conceivable that this paradigm of nuclear coactivation by IRS-1 is conserved in other contexts.…”

“…While the cytosolic/membrane localization of IRS-1 in association with the insulin and insulin-like growth factor 1 (IGF-1) receptors is widely known, nuclear accumulation of IRS-1 following stimulation with IGF-1 has also been reported in the literature (Tu et al 2002). Once inside the nucleus, IRS-1 is capable of associating with and activating specific promoters, although IRS-1 does not contain a DNA-binding motif (Wu et al 2008). We reasoned that Wnt3A treatment may lead to an analogous set of events if the overall induction of IRS-1 increases the nuclear IRS-1 concentration as a secondary consequence.…”

Characterization of a Novel Primary Mammary Tumor Cell Line Reveals that Cyclin D1 Is Regulated by the Type I Insulin-Like Growth Factor Receptor

“…Overexpression of IGF-IR seems to regulate cyclin D1 at the transcriptional level (increased gene expression on DNA microarray). Interestingly, transcriptional regulation of cyclin D1 following IGF-IR activation was recently found to be associated with nuclear translocation of the major IGF-IR docking protein insulin receptor substrate 1, followed by activation of the cyclin D1 promoter (48). Thus, IGF-IR may regulate cyclin D1 levels through insulin receptor substrate-1 activation.…”