ADENOMATOUS POLYPOSIS-COLI TUMOR-SUPPRESSOR PROTEIN HAS SIGNALING ACTIVITY IN XENOPUS-LAEVIS EMBRYOS RESULTING IN THE INDUCTION OF AN ECTOPIC DORSOANTERIOR AXIS

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gen e are linked to both familial and sporadic human colon cancer, So far, a clear biological function for the APC gene product has not been det ermined. We assayed the activity of APC in the early Xenopus embryo, w hich has been established as a good model for the analysis of the sign aling activity of the APC-associated protein beta-catenin, When expres sed in the future ventral side of a four-eel embryo, full-length APC i nduced a secondary dorsoanterior axis and the induction of the homeobo x gene Siamois. This is similar to the phenotype previously observed f or ectopic beta-catenin expression. In fact, axis induction by APC req uired the availability of cytosolic beta-catenin. These results indica te that APC has signaling activity in the early Xenopus embryo. Signal ing activity resides in the central domain of the protein, a part of t he molecule that is missing in most of the truncating APC mutations in colon cancer. Signaling by APC in Xenopus embryos is not accompanied by detectable changes in expression levels of beta-catenin, indicating that it has direct positive signaling activity in addition to its rol e in beta-catenin turnover, From these results we propose a model in w hich APC acts as part of the Wnt/beta-catenin signaling pathway, eithe r upstream of, or in conjunction with, beta-catenin.