• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

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

Authors

  • Bommer GT
  • Feng Y
  • Iura A
  • Giordano TJ
  • Kuick R
  • Kadikoy H
  • Sikorski D
  • Wu R
  • Cho KR
  • Fearon ER

Journal

The Journal of biological chemistry

Publication Data

January 15, 2010

Associated Grants

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

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