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

Mol Cell. 2001 May;7(5):927-36. doi: 10.1016/s1097-2765(01)00241-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenomatous Polyposis Coli Protein
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / pharmacology
  • Cell Cycle / drug effects
  • Cytoskeletal Proteins / metabolism*
  • Cytoskeletal Proteins / physiology
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / drug effects
  • Embryo, Nonmammalian
  • GTP-Binding Proteins / pharmacology
  • Glycogen Synthase Kinase 3
  • Humans
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / pharmacology*
  • Phosphorylation / drug effects
  • Protein Binding
  • Signal Transduction / drug effects
  • Trans-Activators*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / pharmacology*
  • Ubiquitin-Protein Ligases
  • Xenopus
  • Xenopus Proteins*
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins

Substances

  • Adenomatous Polyposis Coli Protein
  • BTRC protein, Xenopus
  • BTRC protein, human
  • CTNNB1 protein, Xenopus
  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Trans-Activators
  • Tumor Suppressor Protein p53
  • Xenopus Proteins
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • GTP-Binding Proteins