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

Oncogene. 2008 Jan 10;27(3):397-403. doi: 10.1038/sj.onc.1210636. Epub 2007 Aug 13.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Chromatin Immunoprecipitation
  • Cyclin D1 / genetics*
  • DNA, Ribosomal / genetics*
  • Genes, Reporter
  • Genes, cdc*
  • Insulin Receptor Substrate Proteins
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Mice
  • Phosphorylation
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / genetics*
  • T Cell Transcription Factor 1 / metabolism
  • Transcriptional Activation*

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA, Ribosomal
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • Proto-Oncogene Proteins c-myc
  • T Cell Transcription Factor 1
  • Cyclin D1