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J. Biol. Chem., Vol. 282, Issue 45, 32582-32590, November 9, 2007

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Micro RNA 145 Targets the Insulin Receptor Substrate-1 and Inhibits the Growth of Colon Cancer Cells^*

Bin Shi, Laura Sepp-Lorenzino, Marco Prisco, Peter Linsley, Tiziana deAngelis, and Renato Baserga¹

From the Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and Merck & Company Inc., Westpoint, Pennsylvania 19486

The insulin receptor substrate-1 (IRS-1), a docking protein for both the type 1 insulin-like growth factor receptor (IGF-IR) and the insulin receptor, is known to send a mitogenic, anti-apoptotic, and anti-differentiation signal. Several micro RNAs (miRs) are suggested by the data base as possible candidates for targeting IRS-1. We show here that one of the miRs predicted by the data base, miR145, whether transfected as a synthetic oligonucleotide or expressed from a plasmid, causes down-regulation of IRS-1 in human colon cancer cells. IRS-1 mRNA is not decreased by miR145, while it is down-regulated by an siRNA targeting IRS-1. Targeting of the IRS-1 3'-untranslated region (UTR) by miR145 was confirmed using a reporter gene (luciferase) expressing the miR145 binding sites of the IRS-1 3'-UTR. In agreement with the role of IRS-1 in cell proliferation, we show that treatment of human colon cancer cells with miR145 causes growth arrest comparable to the use of an siRNA against IRS-1. Taken together, these results identify miR145 as a micro RNA that down-regulates the IRS-1 protein, and inhibits the growth of human cancer cells.

Received for publication, April 3, 2007 , and in revised form, September 7, 2007.

^* This work was supported by Grants CA 089640 and CA 78890 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data and Figs. S1–S3.

¹ To whom correspondence should be addressed: Dept. of Cancer Biology, Thomas Jefferson University, Kimmel Cancer Center, 233 S. 10th St., 624 BLSB, Philadelphia, PA 19107. Tel.: 215-503-4507; Fax: 215-923-0249; E-mail: b_lupo{at}mail.jci.tju.edu.

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