Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein.
The adenomatous polyposis coli (APC) tumor-suppressor protein, together with Axin and GSK3beta, 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 GSK3beta-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.
Pubmed ID: 11389840 RIS Download
Adenomatous Polyposis Coli Protein | Animals | Calcium-Calmodulin-Dependent Protein Kinases | Cell Cycle | Cytoskeletal Proteins | Embryo, Mammalian | Embryo, Nonmammalian | GTP-Binding Proteins | Glycogen Synthase Kinase 3 | Humans | Neoplasm Proteins | Nuclear Proteins | Phosphorylation | Protein Binding | Signal Transduction | Trans-Activators | Tumor Cells, Cultured | Tumor Suppressor Protein p53 | Ubiquitin-Protein Ligases | Xenopus | Xenopus Proteins | beta Catenin | beta-Transducin Repeat-Containing Proteins