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J. Biol. Chem., Vol. 280, Issue 33, 29912-29920, August 19, 2005

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Functional Significance of Type 1 Insulin-like Growth Factor-mediated Nuclear Translocation of the Insulin Receptor Substrate-1 and -Catenin^*

Jia Chen, An Wu, Hongzhi Sun, Robert Drakas, Cecilia Garofalo, Sandra Cascio, Eva Surmacz, and Renato Baserga¶

From the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and the Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, Pennsylvania 19122

Previous work has shown that the transcriptional regulator -catenin can translocate to the nuclei when cells are stimulated with the type 1 insulin-like growth factor (IGF-1). We show by immunocoprecipitation and by confocal microscopy that -catenin binds to and co-localizes with the insulin receptor substrate-1 (IRS-1), a docking protein for both the insulin and the IGF-1 receptors. IRS-1 is required for IGF-1-mediated nuclear translocation of -catenin, resulting in the activation of the -catenin target genes. IGF-1-mediated nuclear translocation of -catenin is facilitated by the nuclear translocation of IRS-1. Both IRS-1 and -catenin are recruited to the cyclin D1 promoter, an established target for -catenin, but only IRS-1 is recruited to the ribosomal DNA (rDNA) promoter. UBF proteins (known to interact with both IRS-1 and -catenin) are also detectable in the cyclin D1 and rDNA promoters. These results indicate that IRS-1 (activated by the IGF-1 receptor) is one of several proteins that regulate the subcellular localization and activity of -catenin. The ability of IRS-1 to localize to both RNA polymerase II (with -catenin) and RNA polymerase I-regulated promoters suggest an explanation for the effect of IRS-1 on both cell growth in size and cell proliferation. This possibility is supported by the demonstration that enforced nuclear localization of IRS-1 causes nuclear translocation of -catenin and transformation of normal mouse embryo fibroblasts (colony formation in soft agar).

Received for publication, April 25, 2005 , and in revised form, June 9, 2005.

^* This work was supported by Grants CA089640 and AG20956 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th St., 624 Bluemle Life Sciences Bldg., Philadelphia, PA 19107. Tel.: 215-503-4507; Fax: 215-923-0249; E-mail: B_lupo{at}mail.jci.tju.edu.

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