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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

Authors

  • Liu J
  • Stevens J
  • Rote CA
  • Yost HJ
  • Hu Y
  • Neufeld KL
  • White RL
  • Matsunami N

Journal

Molecular cell

Publication Data

May 6, 2001

Associated Grants

  • Agency: NCI NIH HHS, Id: 5PO1 CA73992-02

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