Abstract
Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the β-catenin-driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox sensors, rendering bolus redox signal-dosing methods uninformative. Herein we examine the ramifications of single-protein target-specific AR upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits β-catenin/Wnt. The magnitude and mechanism of this negative regulation are dependent on the direct interaction between β-catenin N terminus and β-TrCP1 (an antagonist of both Nrf2 and β-catenin), and independent of binding between Nrf2 and β-TrCP1. Intriguingly, β-catenin positively regulates AR. Because AR is a negative regulator of Wnt regardless of β-catenin N terminus, this switch of function is likely sufficient to establish a new Wnt/AR equilibrium during tumorigenesis.
Keywords:
4-hydroxynonenal; HaloTag; Keap1-Nrf2-antioxidant response; reactive electrophile response; redox signaling; signaling crosstalk; β-TrCP; β-catenin/wnt signaling.
Copyright © 2017 Elsevier Ltd. All rights reserved.
MeSH terms
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Aldehydes / toxicity
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Antioxidants / chemistry
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Antioxidants / metabolism
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Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
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Glycogen Synthase Kinase 3 beta / genetics
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Glycogen Synthase Kinase 3 beta / metabolism
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HEK293 Cells
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HeLa Cells
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Humans
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Kelch-Like ECH-Associated Protein 1 / chemistry
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Kelch-Like ECH-Associated Protein 1 / metabolism
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NF-E2-Related Factor 2 / antagonists & inhibitors
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NF-E2-Related Factor 2 / metabolism
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PTEN Phosphohydrolase / antagonists & inhibitors
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Protein Binding
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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RNA Interference
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RNA, Small Interfering / metabolism
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Wnt Proteins / metabolism*
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Wnt Signaling Pathway / drug effects
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beta Catenin / antagonists & inhibitors
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beta Catenin / metabolism
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beta-Transducin Repeat-Containing Proteins / antagonists & inhibitors
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beta-Transducin Repeat-Containing Proteins / genetics
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beta-Transducin Repeat-Containing Proteins / metabolism*
Substances
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Aldehydes
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Antioxidants
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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Protein Isoforms
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RNA, Small Interfering
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Wnt Proteins
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beta Catenin
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beta-Transducin Repeat-Containing Proteins
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tert-4-hydroxy-2-nonenal
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Glycogen Synthase Kinase 3 beta
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PTEN Phosphohydrolase