Tumour suppressor TRIM33 targets nuclear β-catenin degradation.
Aberrant activation of β-catenin in the nucleus has been implicated in a variety of human cancers, but the fate of nuclear β-catenin is unknown. Here we demonstrate that the tripartite motif-containing protein 33 (TRIM33), acting as an E3 ubiquitin ligase, reduces the abundance of nuclear β-catenin protein. TRIM33-mediated β-catenin is ... destabilized and is GSK-3β or β-TrCP independent. TRIM33 interacts with and ubiquitylates nuclear β-catenin. Moreover, protein kinase Cδ, which directly phosphorylates β-catenin at Ser715, is required for the TRIM33-β-catenin interaction. The function of TRIM33 in suppressing tumour cell proliferation and brain tumour development depends on TRIM33-promoted β-catenin degradation. In human glioblastoma specimens, endogenous TRIM33 levels are inversely correlated with β-catenin. In summary, our findings identify TRIM33 as a tumour suppressor that can abolish tumour cell proliferation and tumorigenesis by degrading nuclear β-catenin. This work suggests a new therapeutic strategy against human cancers caused by aberrant activation of β-catenin.
Mesh Terms:
Animals, Cell Line, Cell Line, Tumor, Cell Proliferation, Humans, Mice, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Ubiquitination, beta Catenin
Animals, Cell Line, Cell Line, Tumor, Cell Proliferation, Humans, Mice, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Ubiquitination, beta Catenin
Nat Commun
Date: Feb. 03, 2015
PubMed ID: 25639486
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