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