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

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 exa...

Full description

Saved in:
Bibliographic Details
Published in:Genes & development 2016-01, Vol.30 (1), p.52-63
Main Authors: Cheung, Eric C, Lee, Pearl, Ceteci, Fatih, Nixon, Colin, Blyth, Karen, Sansom, Owen J, Vousden, Karen H
Format: Article
Language:English
Subjects:
Adenomatous Polyposis Coli Protein - genetics
Animals
Apoptosis Regulatory Proteins
Cell Proliferation - physiology
Gene Expression Regulation, Neoplastic - genetics
Intestines - cytology
Mice
Neuropeptides - metabolism
Phosphoric Monoester Hydrolases
Proteins - metabolism
rac1 GTP-Binding Protein - metabolism
Reactive Oxygen Species - metabolism
Research Paper
Wnt Proteins - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.271130.115