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PMID:11389840

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Citation

Liu, J, Stevens, J, Rote, CA, Yost, HJ, Hu, Y, Neufeld, KL, White, RL and Matsunami, N (2001) Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol. Cell 7:927-36

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.

Links

PubMed

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:APC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IUQ4

F

Seeded From UniProt

complete

HUMAN:SIAH1

enables

GO:0008022: protein C-terminus binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25054

F

Seeded From UniProt

complete

HUMAN:SIAH1

involved_in

GO:0030163: protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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