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J. Biol. Chem., Vol. 279, Issue 50, 52218-52226, December 10, 2004

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A Loss of Insulin-like Growth Factor-2 Imprinting Is Modulated by CCCTC-binding Factor Down-regulation at Senescence in Human Epithelial Cells^*

Vivian X. Fu, Steven R. Schwarze, Michelle L. Kenowski, Scott LeBlanc¶, John Svaren, and David F. Jarrard||**

From the Department of Surgery, ^||Department of Environmental and Molecular Toxicology, and Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53792

The imprinted insulin-like growth factor-2 (IGF2) gene is an auto/paracrine growth factor expressed only from the paternal allele in adult tissues. In tissues susceptible to aging-related cancers, including the prostate, a relaxation of IGF2 imprinting is found, suggesting a permissive role for epigenetic alterations in cancer development. To determine whether IGF2 imprinting is altered in cellular aging and senescence, human prostate epithelial and urothelial cells were passaged serially in culture to senescence. Allelic analyses using an IGF2 polymorphism demonstrated a complete conversion of the IGF2 imprint status from monoallelic to biallelic, in which the development of senescence was associated with a 10-fold increase in IGF2 expression. As a mechanism, a 2-fold decrease in the binding of the enhancer-blocking element CCCTC-binding factor (CTCF) within the intergenic IGF2-H19 region was found to underlie this switch to biallelic IGF2 expression in senescent cells. This decrease in CTCF binding was associated with reduced CTCF expression in senescent cells. No de novo increases in methylation at the IGF2 CTCF binding site were seen. The forced down-regulation of CTCF expression using small interfering RNA in imprinted prostate cell lines resulted in an increase in IGF2 expression and a relaxation of imprinting. Our data suggest a novel mechanism for IGF2 imprinting regulation, that is, the reduction of CTCF expression in the control of IGF2 imprinting. We also demonstrate that altered imprinting patterns contribute to changes in gene expression in aging cells.

Received for publication, May 5, 2004 , and in revised form, September 21, 2004.

^* This work was supported in part by National Institutes of Health Grants K08CA76184 and R01CA97131, University of Wisconsin George M. O'Brien Urology Research Center (1P50DK065303), Department of Defense Prostate Cancer Research Program (DAMD17-02-1-0163), the John Livesey endowment, and the American Federation for Aging Research. 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.

^¶ Supported through a National Institutes of Health training grant (T32 GM08688) to the Molecular and Cellular Pharmacology Training Program.

^** To whom correspondence should be addressed: University of Wisconsin Comprehensive Cancer Center, 600 Highland Ave., K6/530, Madison, WI 53792. Tel.: 608-265-2225; Fax: 608-265-8133. E-mail: jarrard{at}surgery.wisc.edu.

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