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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Antioxidants / metabolism*
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Binding, Competitive / physiology
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Chromosomes, Human, X / genetics
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism*
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2 / metabolism*
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Phosphorylation / physiology
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RNA, Small Interfering / genetics
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Serine / metabolism
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Transcriptional Activation / physiology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitination / physiology
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Wilms Tumor / genetics
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Wilms Tumor / metabolism*
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beta-Transducin Repeat-Containing Proteins / metabolism
Substances
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AMER1 protein, human
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Adaptor Proteins, Signal Transducing
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Antioxidants
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BTRC protein, human
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Intracellular Signaling Peptides and Proteins
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KEAP1 protein, human
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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RNA, Small Interfering
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Tumor Suppressor Proteins
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beta-Transducin Repeat-Containing Proteins
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Serine