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

Oncogene volume 27, pages 397–403 (2008)Cite this article

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.

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Acknowledgements

This work was supported by grants from the National Institutes of Health, CA78890 and CA08640.

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  1. Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    A Wu, J Chen & R Baserga

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  1. A Wu
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Correspondence to R Baserga.

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Wu, A., Chen, J. & Baserga, R. Nuclear insulin receptor substrate-1 activates promoters of cell cycle progression genes. Oncogene 27, 397–403 (2008). https://doi.org/10.1038/sj.onc.1210636

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