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.
Mesh Terms:
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
Mol. Cell
Date: May. 01, 2001
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