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Molecular and Cellular Biology, December 2008, p. 7368-7379, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00744-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Genome-Wide Screen for β-Catenin Binding Sites Identifies a Downstream Enhancer Element That Controls c-Myc Gene Expression {triangledown}

Gregory S. Yochum,* Ryan Cleland, and Richard H. Goodman

Vollum Institute and Department of Medicine, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239

Received 8 May 2008/ Returned for modification 27 June 2008/ Accepted 1 October 2008

Mutations in components of the Wnt signaling pathway initiate colorectal carcinogenesis by deregulating the β-catenin transcriptional coactivator. β-Catenin activation of one target in particular, the c-Myc proto-oncogene, is required for colon cancer pathogenesis. β-Catenin is known to regulate c-Myc expression via sequences upstream of the transcription start site. Here, we report that a more robust β-catenin binding region localizes 1.4 kb downstream from the c-Myc transcriptional stop site. This site was discovered using a genome-wide method for identifying transcription factor binding sites termed serial analysis of chromatin occupancy. Chromatin immunoprecipitation-scanning assays demonstrate that the 5' enhancer and the 3' binding element are the only β-catenin and TCF4 binding regions across the c-Myc locus. When placed downstream of a simian virus 40-driven promoter-luciferase construct, the 3' element activated luciferase transcription when introduced into HCT116 cells. c-Myc transcription is negligible in quiescent HCT116 cells but is induced when cells reenter the cell cycle after the addition of mitogens. Using these cells, we found that β-catenin and TCF4 occupancy at the 3' enhancer precede occupancy at the 5' enhancer. Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription. Our findings indicate that a downstream enhancer element provides the principal regulation of c-Myc expression.

* Corresponding author. Mailing address: Vollum Institute and Department of Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Phone: (503) 494-4676. Fax: (503) 494-4353. E-mail: yochumg{at}ohsu.edu

{triangledown} Published ahead of print on 13 October 2008.

Molecular and Cellular Biology, December 2008, p. 7368-7379, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00744-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Saadeddin, A., Babaei-Jadidi, R., Spencer-Dene, B., Nateri, A. S. (2009). The Links between Transcription, {beta}-catenin/JNK Signaling, and Carcinogenesis. Mol Cancer Res 7: 1189-1196 [Abstract] [Full Text]  


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