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J. Biol. Chem., Vol. 278, Issue 39, 37231-37240, September 26, 2003

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The IGF2 Receptor Is a USF2-specific Target in Nontumorigenic Mammary Epithelial Cells but Not in Breast Cancer Cells^*

Marilyn N. Szentirmay , Hui-Xin Yang , Snehalata A. Pawar , Charles Vinson  and Michèle Sawadogo  ¶

From the Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 and aboratory of Biochemistry, NCI, National Institutes of Health, Bethesda, Maryland 20892

The antiproliferative activities of the USF proteins and the frequent loss of USF function in cancer cells suggest a role for these ubiquitous transcription factors in tumor suppression. However, the cellular targets that mediate the effects of USF on cellular proliferation and transformation remain uncharacterized. IGF2R, with multiple functions in both normal growth and cancer, was investigated here as a possible USF target in both nontumorigenic and tumorigenic breast cell lines. The 5'-flanking sequences of the human IGF2R gene contain multiple, highly conserved E boxes almost identical to the consensus USF DNA-binding sequence. These E boxes were found to be essential for IGF2R promoter activity in the nontumorigenic mammary epithelial cell line MCF-10A. USF1 and USF2 bound the IGF2R promoter in vitro, and both USF1 and USF2, but not c-Myc, were present within the IGF2R promoter-associated chromatin in vivo. Overexpressed USF2, but not USF1, transactivated the IGF2R promoter, and IGF2R mRNA was markedly decreased by expression of a USF-specific dominant negative mutant, identifying IGF2R as a USF2 target. IGF2R promoter-driven expression was USF-independent in both MCF-7 and MDA-MB-231 breast cancer cell lines, suggesting that a defect in USF function may contribute to down-regulation of IGF2R expression in cancer cells.

Received for publication, June 3, 2003 , and in revised form, July 10, 2003.

^* This work was supported by Grants 9866 from the Susan G. Komen Breast Cancer Foundation, CA79578 from the National Institutes of Health, and G-1195 from the Robert A. Welch Foundation. 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. Tel.: 713-794-1281; Fax: 713-794-4295; E-mail: msawadog{at}mdanderson.org.

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