Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
Cell Chem Biol. 2017 Aug 17;24(8):944-957.e7. doi: 10.1016/j.chembiol.2017.06.009. Epub 2017 Jul 20.
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.
在肿瘤发生过程中，Wnt 和抗氧化反应 (AR) 同时被过度激活的现象经常出现。然而，β-连环蛋白驱动的 Wnt 和 Nrf2 驱动的 AR 如何相互调节彼此的机制仍不清楚。由于这两条通路中的许多参与者都是氧化还原传感器，因此使用大量氧化还原信号处理方法也无济于事。在此，我们研究了在各种敲低细胞系中特异性上调单一蛋白靶标对 AR 的影响。我们的数据记录表明，Nrf2/AR 强烈抑制β-连环蛋白/Wnt。这种负调控的幅度和机制取决于β-连环蛋白 N 端与β-TrCP1（Nrf2 和β-连环蛋白的拮抗剂）之间的直接相互作用，而与 Nrf2 和β-TrCP1 之间的结合无关。有趣的是，β-连环蛋白正向调节 AR。由于 AR 是 Wnt 的负调节剂，与β-连环蛋白 N 端无关，因此这种功能转换足以在肿瘤发生过程中建立新的 Wnt/AR 平衡。
