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J Biol Chem. 2012 Feb 24;287(9):6539-50. doi: 10.1074/jbc.M111.316471. Epub 2012 Jan 3.

Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein.

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1
Howard Hughes Medical Institute, Department of Pharmacology, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA.

Abstract

WTX is a tumor suppressor protein that is lost or mutated in up to 30% of cases of Wilms tumor. Among its known functions, WTX interacts with the β-transducin repeat containing family of ubiquitin ligase adaptors and promotes the ubiquitination and degradation of the transcription factor β-catenin, a key control point in the WNT/β-catenin signaling pathway. Here, we report that WTX interacts with a second ubiquitin ligase adaptor, KEAP1, which functions to regulate the ubiquitination of the transcription factor NRF2, a key control point in the antioxidant response. Surprisingly, we find that unlike its ability to promote the ubiquitination of β-catenin, WTX inhibits the ubiquitination of NRF2. WTX and NRF2 compete for binding to KEAP1, and thus loss of WTX leads to rapid ubiquitination and degradation of NRF2 and a reduced response to cytotoxic insult. These results expand our understanding of the molecular mechanisms of WTX and reveal a novel regulatory mechanism governing the antioxidant response.

PMID:
22215675
PMCID:
PMC3307315
DOI:
10.1074/jbc.M111.316471
[Indexed for MEDLINE]
Free PMC Article
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