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Molecular and Cellular Biology, October 2009, p. 5306-5315, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.01745-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Acute Overexpression of Myc in Intestinal Epithelium Recapitulates Some but Not All the Changes Elicited by Wnt/β-Catenin Pathway Activation {triangledown}

Andrew J. Finch ,{dagger},# Laura Soucek,{dagger} Melissa R. Junttila, Lamorna Brown Swigart, and Gerard I. Evan*

Department of Pathology and UCSF Helen Diller Family Comprehensive Cancer Center, 513 Parnassus Avenue, San Francisco, California 94143-0502

Received 13 November 2008/ Returned for modification 28 January 2009/ Accepted 17 July 2009

The Myc transcription factor is a potent inducer of proliferation and is required for Wnt/β-catenin signaling in intestinal epithelium. Since deregulation of the Wnt/β-catenin pathway is a prerequisite for nonhereditary intestinal tumorigenesis, we asked whether activation of Myc recapitulates the tumorigenic changes that are driven by constitutive Wnt/β-catenin pathway signaling following adenomatous polyposis coli (APC) inactivation. Using mice in which expression of MycERTAM, a reversibly switchable form of Myc, is expressed transgenically in intestinal epithelium, we define the acute changes that follow Myc activation as well as subsequent deactivation. Myc activation reversibly recapitulates many, but not all, aspects of APC inactivation, including increased proliferation and apoptosis and loss of goblet cells. However, whereas APC inactivation induces redistribution of Paneth cells, direct Myc activation triggers their rapid attrition. Moreover, direct Myc activation engages the ARF/p53/p21cip1 tumor suppressor pathway, whereas deregulation of Wnt/β-catenin signaling does not. These observations illustrate key differences in oncogenic impact in intestinal epithelium of direct Myc activation and indirect Myc activation via the Wnt/β-catenin pathway. Furthermore, the in situ dedifferentiation of mature goblet cells that Myc induces indicates a novel cross talk between the Wnt/β-catenin and Notch signaling pathways.

* Corresponding author. Mailing address: Department of Pathology and UCSF Helen Diller Family Comprehensive Cancer Center, 513 Parnassus Avenue, San Francisco, CA 94143-0502. Phone: (415) 514-0438. Fax: (415) 514-0878. E-mail: gerard.evan{at}ucsf.edu

{triangledown} Published ahead of print on 27 July 2009.

{dagger} These authors contributed equally to this work.

# Present address: Medical Research Council Laboratory of Molecular Biology, PNAC Division, Hills Road, Cambridge CB2 0QH, United Kingdom.

Molecular and Cellular Biology, October 2009, p. 5306-5315, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.01745-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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