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J. Biol. Chem., Vol. 282, Issue 2, 871-878, January 12, 2007

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An Antisense Transcript Induced by Wnt/-Catenin Signaling Decreases E2F4^*

Gregory S. Yochum¹, Ryan Cleland, Shannon McWeeney^¶, and Richard H. Goodman

From the Vollum Institute and the Division of Biostatistics, Department of Public Health and Preventative Medicine, and the ^¶OHSU Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239

Wnt signaling induces the nuclear accumulation of -catenin and transcription of specific target genes via the DNA-binding proteins TCF/Lef. Although all known -catenin target genes encode proteins, genome-wide RNA profiling studies indicate that many transcripts do not have this capability. Transcription factor-binding sites associated with these noncoding transcripts can be identified using unbiased techniques such as serial analysis of chromatin occupancy (SACO). We used this method to identify a -catenin-regulated antisense RNA expressed in HCT116 colorectal carcinoma cells, a cellular model of activated -catenin signaling. Genomic signature tags designating putative -catenin-binding sites mapped to the 3'-untranslated region (3'-UTR) of the E2F4 gene. We showed that both -catenin and TCF4 bind to the E2F4 3'-UTR site in vivo, inducing expression of an E2F4 antisense transcript. LiCl, which mimics Wnt signaling, also induced expression of the E2F4 antisense transcript and decreased E2F4 protein levels. This effect was blocked by a cDNA expressing the E2F4 3'-UTR sense strand. The antisense-mediated decrease in E2F4 protein was reflected by reduced E2F4 association with specific target genes, including CCNA2, CDC2, PCNA, and Rad54. We propose that Wnt/-catenin signaling may contribute to colorectal carcinogenesis by reducing the level of the E2F4 cell cycle repressor via an antisense mechanism.

Received for publication, October 4, 2006 , and in revised form, November 13, 2006.

^* This work was supported by grants from the division of Hematology and Oncology (Oregon Health and Science University) and 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 methods.

¹ To whom correspondence should be addressed: Oregon Health and Science University, Vollum Institute, 3181 Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-4676; Fax: 503-494-4353; E-mail: yochumg{at}ohsu.edu.

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