Siah-1 mediates a novel β-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein

The adenomatous polyposis coil (APC) tumor-suppressor protein, together with Axin and GSK3 beta, forms a Wnt-regulated signaling complex that mediates phosphorylation-dependent degradation of beta -catenin by the proteasome. Siah-1, the human homolog of Drosophila seven in absentia, is a p53-inducible mediator of cell cycle arrest, tumor suppression, and apoptosis. We have now found that Siah-1 interacts with the carboxyl terminus of APC and promotes degradation of beta -catenin in mammalian cells. The ability of Siah-1 to downregulate beta -catenin signaling was also demonstrated by hypodorsalization of Xenopus embryos. Unexpectedly, degradation of beta -catenin by Siah-1 was independent of GSK3 beta -mediated phosphorylation and did not require the F box protein beta -TrCP. These results indicate that APC and Siah-1 mediate a novel beta -catenin degradation pathway linking p53 activation to cell cycle control.