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

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.

Pubmed ID: 19843521 RIS Download

Mesh terms: Animals | Cell Line, Tumor | Cell Transformation, Neoplastic | Gene Expression Regulation, Neoplastic | Humans | Insulin Receptor Substrate Proteins | Mice | Mutation | Neoplasms | Oncogenes | Phenotype | Rats | Signal Transduction | Wnt Proteins | beta Catenin

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Associated grants

  • Agency: NCI NIH HHS, Id: R01CA94172
  • Agency: NCI NIH HHS, Id: CA085463
  • Agency: NCI NIH HHS, Id: P30 CA046592
  • Agency: NCI NIH HHS, Id: R01 CA085463
  • Agency: NCI NIH HHS, Id: CA094172
  • Agency: NCI NIH HHS, Id: R01 CA094172
  • Agency: NCI NIH HHS, Id: CA046592

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