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

Abstract

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 MycER^TAM, 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/p21^cip1 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.

ACKNOWLEDGMENTS

This study was supported by NIH grant RO1 CA98018, funds from Daiichi Corp., a Stewart Trust Cancer Research Award, and the Sandler Family Foundation (all to G.I.E.). M.R.J. is funded by an Enrique Cepero Fellowship of the Damon Runyon Cancer Research Foundation.

We are most grateful to Fanya Rostker for her technical assistance and to our colleagues in the Evan lab for their invaluable criticism and advice.