Nuclear insulin receptor substrate-1 activates promoters of cell cycle progression genes.
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.
Wu
A
A
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Chen
J
J
Baserga
R
R
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019938:Cyclin D1 / Q000235:genetics*; D004275:DNA, Ribosomal / Q000235:genetics*; D017930:Genes, Reporter; D018816:Genes, cdc; D055504:Insulin Receptor Substrate Proteins; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D051822:T Cell Transcription Factor 1 / Q000378:metabolism; D015533:Transcriptional Activation
D048868:Adaptor Proteins, Signal Transducing; D004275:DNA, Ribosomal; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D016271:Proto-Oncogene Proteins c-myc; D051822:T Cell Transcription Factor 1; D019938:Cyclin D1