Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine

Cheung, E., Lee, P., Ceteci, F., Nixon, C., Blyth, K. , Sansom, O. and Vousden, K. (2016) Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine. Genes and Development, 30(1), pp. 52-63. (doi: 10.1101/gad.271130.115) (PMID:26679840) (PMCID:PMC4701978)

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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.

Item Type:Articles
Additional Information:We thank the Beatson Institute facilities at the Cancer Research UK Beatson Institute (C596/A17196), the Cancer Research UK GlasgowCentre (C596/A18076), and the Beatson Institute Histology Service.We also thank Daniel Murphy for providing access to the Myc-dependent lung cancer model. We are grateful for funding from Cancer Research UK grant C596/A10419, European Research Council grant 322842-METABOp53, and a Medical Research Council studentship.
Glasgow Author(s) Enlighten ID:Blyth, Professor Karen and Cheung, Mr Eric and Nixon, Mr Colin and Vousden, Karen and Ceteci, Dr Fatih and Sansom, Professor Owen
Authors: Cheung, E., Lee, P., Ceteci, F., Nixon, C., Blyth, K., Sansom, O., and Vousden, K.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Genes and Development
Publisher:Cold Spring Harbor Laboratory Press
ISSN (Online):1549-5477
Copyright Holders:Copyright © 2016 Cheung et al.
First Published:First published in Genes and Development 30(1):52-63
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CAN-RES-UK)18076RI CANCER SCIENCES