IRS1 regulation by wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype

Bommer, Guido [UCL] Feng, Ying Iura, Ayaka Giordano, Thomas J Kuick, Rork Kadikoy, Huseyin Sikorski, Deanna Wu, Rong Cho, Kathleen R Fearon, Eric R et al.[show all]

Dysregulation of beta-catenin levels and localization and constitutive activation of beta-catenin/TCF (T cell factor)-regulated gene expression occurs in many cancers, including the majority of colorectal carcinomas (CRCs) and a subset of ovarian endometrioid adenocarcinomas (OEAs). 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 upregulated genes upon ectopic expression of a mutant, constitutively active form of beta-catenin in the rat kidney epithelial cell line RK3E. We demonstrate that 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 CRCs and OEAs. Using an shRNA approach to abrogate IRS1 expression and function, we found 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.