IRS1 Regulation by Wnt/ -Catenin Signaling and Varied Contribution of IRS1 to the Neoplastic Phenotype

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2009; 285(3):1928-38. DOI: 10.1074/jbc.M109.060319
Source: PubMed


Dysregulation of beta-catenin levels and localization and constitutive activation of beta-catenin/TCF (T cell factor)-regulated gene expression occur in many cancers, including the majority of colorectal carcinomas and a subset of ovarian endometrioid adenocarcinomas. Based on the results of microarray-based gene expression profiling we found the insulin receptor substrate 1 (IRS1) gene as one of the most highly up-regulated genes upon ectopic expression of a mutant, constitutively active form of beta-catenin in the rat kidney epithelial cell line RK3E. We demonstrate expression of IRS1 can be directly activated by beta-catenin, likely in part via beta-catenin/TCF binding to TCF consensus binding elements located in the first intron and downstream of the IRS1 transcriptional start site. Consistent with the proposal that beta-catenin is an important regulator of IRS1 expression in vivo, we observed that IRS1 is highly expressed in many cancers with constitutive stabilization of beta-catenin, such as colorectal carcinomas and ovarian endometrioid adenocarcinomas. Using a short hairpin RNA approach to abrogate IRS1 expression and function, we found that IRS1 function is required for efficient de novo neoplastic transformation by beta-catenin in RK3E cells. Our findings add to the growing body of data implicating IRS1 as a critical signaling component in cancer development and progression.

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    • "On the other hand, IRS-1 itself is a downstream target gene of β-catenin, which regulates IRS-1 expression in vivo. The interplay between IRS-1 and β-catenin may represent another mechanism promoting cancer initiation (122), and regulating self-renewal and differentiation processes (123). Taken together, these data highlight the existence of a close connection and a positive feed-back loop between the Wnt/β-catenin and IGF signaling, which contribute to oncogenesis and EMT process. "
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    ABSTRACT: Cancer cells frequently exploit the IGF signaling, a fundamental pathway mediating development, cell growth, and survival. As a consequence, several components of the IGF signaling are deregulated in cancer and sustain cancer progression. However, specific targeting of IGF-IR in humans has resulted efficacious only in small subsets of cancers, making researches wondering whether IGF system targeting is still worth pursuing in the clinical setting. Although no definite answer is yet available, it has become increasingly clear that other components of the IGF signaling pathway, such as IR-A, may substitute for the lack of IGF-IR, and induce cancer resistance and/or clonal selection. Moreover, accumulating evidence now indicates that IGF signaling is a central player in the induction/maintenance of epithelial mesenchymal transition (EMT) and cell stemness, two strictly related programs, which play a key role in metastatic spread and resistance to cancer treatments. Here we review the evidences indicating that IGF signaling enhances the expression of transcription factors implicated in the EMT program and has extensive cross-talk with specific pathways involved in cell pluripotency and stemness maintenance. In turn, EMT and cell stemness activate positive feed-back mechanisms causing up-regulation of various IGF signaling components. These findings may have novel translational implications.
    Frontiers in Endocrinology 02/2014; 5:10. DOI:10.3389/fendo.2014.00010
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    • "Since insulin/IGF-1 signaling cross-talks with Wnt [20,37–39], we hypothesized that the impaired insulin/IGF-1 signaling in cerebella of chronic prenatal ethanol exposed rats would be associated with down-regulation of Wnt pathway genes (Figure 1). We first performed exploratory qPCR studies in which the expression levels of 84 Wnt pathway and target genes (Supplementary tables 1 and 2) were compared between pooled samples of P20 control and ethanol-exposed rats (N=3 per group with each sample obtained from different litters) using the same model described in the Materials and Methods section (Supplementary Methods). "
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    ABSTRACT: BackgroundFetal alcohol spectrum disorder (FASD) is associated with deficits in cerebellar function that can persist through adolescence. Previous studies demonstrated striking inhibition of insulin and insulin-like growth factor (IGF) signaling in ethanol-exposed cerebella.ObjectivesWe sought to determine if FASD-induced impairments in motor function were associated with deficits in insulin/IGF signaling in juvenile cerebella. Given the growing evidence that insulin/IGF pathways cross-talk with Notch and Wnt to promote brain development and maturation; we also examined the integrity of canonical Wnt and Notch signaling networks in the brain following chronic prenatal ethanol exposure.MethodsPregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 24% ethanol by caloric content from gestation day 6 through delivery. Pups were subjected to rotarod testing on postnatal days (P) 15–16 and sacrificed on P30. Cerebella were used for molecular and biochemical analysis of insulin/IGF-1, canonical Wnt, and Notch signaling mechanisms.ResultsPrenatal ethanol exposures impaired rotarod performance, inhibited signaling through insulin and IGF-1 receptors, IRS-1, and Akt, increased activation of GSK-3β, and broadly suppressed genes mediating the canonical Wnt and Notch networks.ConclusionsAbnormalities in cerebellar function following chronic prenatal ethanol exposure are associated with inhibition of insulin/IGF, canonical Wnt, and Notch networks that cross-talk via GSK-3β. Effective therapeutic measures for FASD may require multi-pronged support of interrelated signaling networks that regulate brain development.
    Journal of Diabetes & Metabolism 01/2013; 4(1):238.
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    • "Potential crosstalk between Wnt/Rspo and other growth factor signaling mechanisms was implicit in the synergistic up-regulation of multiple genes that participate in insulin/IGF, TGFβ and FGF pathways (Table 3). One of these genes, IRS1, also was identified as a pathophysiologically relevant Wnt/β-catenin target gene in colorectal carcinomas [59]. Up-regulation of insulin/IGF pathway genes, including IGF1, is provocative given the association of IGF signaling and breast cancer [60]. "
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    ABSTRACT: R-spondins (Rspos) comprise a family of four secreted proteins that have important roles in cell proliferation, cell fate determination and organogenesis. Rspos typically exert their effects by potentiating the Wnt/β-catenin signaling pathway. To systematically investigate the impact of Rspo/Wnt on gene expression, we performed a microarray analysis using C57MG mouse mammary epithelial cells treated with recombinant Rspo2 and/or Wnt3a. We observed the up- and down-regulation of several previously unidentified target genes, including ones that encode proteins involved in immune responses, effectors of other growth factor signaling pathways and transcription factors. Dozens of these changes were validated by quantitative real time RT-PCR. Time course experiments showed that Rspo2 typically had little or no effect on Wnt-dependent gene expression at 3 or 6 h, but enhanced expression at 24 h, consistent with biochemical data indicating that Rspo2 acts primarily to sustain rather than acutely increase Wnt pathway activation. Up-regulation of gene expression was inhibited by pre-treatment with Dickkopf1, a Wnt/β-catenin pathway antagonist, and by siRNA knockdown of β-catenin expression. While Dickkopf1 blocked Rspo2/Wnt3a-dependent down-regulation, a number of down-regulated genes were not affected by β-catenin knockdown, suggesting that in these instances down-regulation was mediated by a β-catenin-independent mechanism.
    PLoS ONE 01/2012; 7(1):e29455. DOI:10.1371/journal.pone.0029455 · 3.23 Impact Factor
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