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.
Liu
J
J
Department of Oncological Sciences, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
Stevens
J
J
Rote
C A
CA
Yost
H J
HJ
Hu
Y
Y
Neufeld
K L
KL
White
R L
RL
Matsunami
N
N
D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism* / Q000502:physiology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects; D004625:Embryo, Nonmammalian; D019204:GTP-Binding Proteins / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases; D014981:Xenopus; D029867:Xenopus Proteins; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D000098563:Seven in Absentia Proteins
D025601:Adenomatous Polyposis Coli Protein; C471646:BTRC protein, Xenopus; C471644:BTRC protein, human; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D029867:Xenopus Proteins; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D019204:GTP-Binding Proteins