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Cell Chem Biol. 2017 Aug 17;24(8):944-957.e7. doi: 10.1016/j.chembiol.2017.06.009. Epub 2017 Jul 20.

β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling.

Author information

1
Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
2
Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: ya222@cornell.edu.

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

PMID:
28736239
PMCID:
PMC5634333
DOI:
10.1016/j.chembiol.2017.06.009
[Indexed for MEDLINE]
Free PMC Article

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