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

Abstract

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.

Modulating the therapeutic response of tumours to dietary serine and glycine starvation

“…While the response to metformin is dose-dependent, our data support the results of in vitro studies that show that manipulating ROS can modulate the response of tumours to SG starvation 7 . To test directly whether increasing ROS in vivo could enhance the anti-tumour effect of the SG-free diet, we used Tigar −/− mice that do not express Tigar, a protein that can support tumour development by limiting ROS 23,24,25,26 . While Eμ-Myc expression on this mixed strain background caused mice to die of lymphoma more rapidly than pure BL6 Eμ-Myc mice (shown in Fig.…”

Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes

“…Their radioactivity was measured in a Beckman LS6500 scintillation counter. The radioactivity of 14 CO2 from [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]-glucose was used as a measurement of the carbon flux through the PPP enzyme, 6-phosphogluconate dehydrogenase. PPP-dependent CO2 production was calculated as the difference between 14 CO2 derived from [1-14 C]-glucose and 14 CO2 derived from [6][7][8][9][10][11][12][13][14] C]-glucose (TCA cycle-dependent CO2 production from glucose).…”

“…The activities of PPP can be decreased by p53, as well as being hyperactivated by oncogenic signaling [2][3][4][5]. Functioning as a fructose-2,6-bisphosphatase (F2,6bPase), TIGAR (TP53-induced glycolysis and apoptosis regulator) can enhance glucose carbon flux to the PPP by dampening glycolysis and is required for the development of intestinal adenomas [6][7][8][9]. As a glycolysis modulator, TIGAR was shown to localize in cytoplasm and associate with mitochondria in complex with the hexokinase HK2 in response to hypoxia [7].…”

Loss of TIGAR Induces Oxidative Stress and Meiotic Defects in Oocytes from Obese Mice

“…However, excessive amounts of ROS can be damaging to the cell, inducing DNA damage, lipid oxidation, and, ultimately, cell death (15). Despite numerous studies suggest that oxidative stress may be a link between maternal obesity and oocyte quality, the potential factors mediating this process remain to be explored.…”

“…Although TIGAR has been reported to function in the control of redox status in several cell types (15,19), its role in mammalian oocytes remains unknown. Moreover, to date, few factor(s) were identified to induce the oxidative stress in HFD oocytes.…”