B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver

doi:10.1073/pnas.0805778105

B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver

^aSchool of Biosciences, University of Cardiff, Cardiff CF10 3AX, United Kingdom;
^bBeatson Institute for Cancer Research, Glasgow G61 1BD, United Kingdom;
^cCentre for Regenerative Medicine, University of Bath, Bath BA2 7AY, United Kingdom; and
^dLeiden University Medical Center, Leiden, The Netherlands, 2333ZA

Edited by Robert N. Eisenman, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved October 13, 2008
↵¹K.R.R., D.A., and V.S.M. contributed equally to this work. (received for review June 18, 2008)

Abstract

Dysregulated Wnt signaling is seen in approximately 30% of hepatocellular carcinomas; thus, finding pathways downstream of the activation of Wnt signaling is key. Here, using cre-lox technology, we deleted the Apc gene in the adult mouse liver and observed a rapid increase in nuclear β-catenin and c-Myc, which is associated with an induction of proliferation that led to hepatomegaly within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes, we analyzed the impact of inactivating APC in the context of deficiency of the potentially key effectors β-catenin and c-Myc. β-catenin loss rescues both the proliferation and hepatomegaly phenotypes after APC loss. However, c-Myc deletion, which rescues the phenotypes of APC loss in the intestine, had no effect on the phenotypes of APC loss in the liver. The consequences of the deregulation of the Wnt pathway within the liver are therefore strikingly different from those observed within the intestine, with the vast majority of Wnt targets being β-catenin-dependent but c-Myc-independent in the liver.

Footnotes

²To whom correspondence should be addressed. E-mail: o.sansom{at}beatson.gla.ac.uk
Author contributions: K.R.R., A.R.C., and O.J.S. designed research; K.R.R., D.A., V.S.M., J.A.W., R.A.R., Z.D.B., and V.M. performed research; K.R.R., D.A., V.S.M., J.A.W., and O.J.S. analyzed data; and A.R.C. and O.J.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0805778105/DCSupplemental.