J. Liu et al., Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein, MOL CELL, 7(5), 2001, pp. 927-936
The adenomatous polyposis coil (APC) tumor-suppressor protein, together wit
h 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-inducib
le mediator of cell cycle arrest, tumor suppression, and apoptosis. We have
now found that Siah-1 interacts with the carboxyl terminus of APC and prom
otes degradation of beta -catenin in mammalian cells. The ability of Siah-1
to downregulate beta -catenin signaling was also demonstrated by hypodorsa
lization of Xenopus embryos. Unexpectedly, degradation of beta -catenin by
Siah-1 was independent of GSK3 beta -mediated phosphorylation and did not r
equire the F box protein beta -TrCP. These results indicate that APC and Si
ah-1 mediate a novel beta -catenin degradation pathway linking p53 activati
on to cell cycle control.