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Vol. 14, No. 11, pp. 1319-1331, June 1, 2000
-Catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of 
-catenin
Division of Medical Genetics and the Cancer Center, Departments of
1 Internal Medicine, 2 Human Genetics, and
3 Pathology and the 4 Program in Cellular and
Molecular Biology, University of Michigan School of Medicine, Ann
Arbor, Michigan 48109 USA
-Catenin and 
-catenin
(plakoglobin), vertebrate homologs of Drosophila armadillo,
function in cell adhesion and the Wnt signaling pathway. In colon and
other cancers, mutations in the APC tumor suppressor protein or
-catenin's amino terminus stabilize -catenin, enhancing its ability to activate
transcription of Tcf/Lef target genes. Though
- and -catenin have
analogous structures and functions and like binding to APC, evidence
that -catenin has an important role in cancer
has been lacking. We report here that APC regulates both
- and -catenin and
-catenin functions as an oncogene. In contrast
to -catenin, for which only amino-terminal mutated forms transform RK3E epithelial cells, wild-type and several amino-terminal mutated forms of -catenin had
similar transforming activity. -Catenin's
transforming activity, like -catenin's, was
dependent on Tcf/Lef function. However, in contrast to
-catenin, -catenin
strongly activated c-Myc expression and c-Myc function was
crucial for -catenin transformation. Our
findings suggest APC mutations alter regulation of both
- and -catenin, perhaps explaining why the frequency of APC mutations in colon cancer far exceeds that of -catenin mutations.
Elevated c-Myc expression in cancers with APC defects may be due to
altered regulation of both - and
-catenin. Furthermore, the data imply
- and -catenin may have
distinct roles in Wnt signaling and cancer via differential effects on
downstream target genes.
[Key Words:
-catenin; plakoglobin; -catenin; cancer; Tcf/Lef; c-Myc; Wnt signaling]
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