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

• 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
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.271130.115

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.