Journal
GENES & DEVELOPMENT
Volume 30, Issue 1, Pages 52-63Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.271130.115
Keywords
TIGAR; ROS; RAC1; APC; Wnt; proliferation
Categories
Funding
- Beatson Institute facilities at the Cancer Research UK Beatson Institute [C596/A17196]
- Cancer Research UK Glasgow Centre [C596/A18076]
- Beatson Institute Histology Service
- Cancer Research UK [C596/A10419]
- European Research Council [322842-METABOp53]
- Medical Research Council
- Cancer Research UK [22311, 18274] Funding Source: researchfish
- Medical Research Council [1097363] Funding Source: researchfish
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Reactive oxygen species (ROS) participate in numerous cell responses, including proliferation, DNA damage, and cell death. Based on these disparate activities, both promotion and inhibition of ROS have been proposed for cancer therapy. However, how the ROS response is determined is not clear. We examined the activities of ROS in a model of Apc deletion, where loss of the Wnt target gene Myc both rescues APC loss and prevents ROS accumulation. Following APC loss, Myc has been shown to up-regulate RAC1 to promote proliferative ROS through NADPH oxidase (NOX). However, APC loss also increased the expression of TIGAR, which functions to limit ROS. To explore this paradox, we used three-dimensional (3D) cultures and in vivo models to show that deletion of TIGAR increased ROS damage and inhibited proliferation. These responses were suppressed by limiting damaging ROS but enhanced by lowering proproliferative NOX-derived ROS. Despite having opposing effects on ROS levels, loss of TIGAR and RAC1 cooperated to suppress intestinal proliferation following APC loss. Our results indicate that the pro-and anti-proliferative effects of ROS can be independently modulated in the same cell, with two key targets in the Wnt pathway functioning to integrate the different ROS signals for optimal cell proliferation.
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