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.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Cheung EC,Lee P,Ceteci F,Nixon C,Blyth K,Sansom OJ,Vousden KHdoi
10.1101/gad.271130.115subject
Has Abstractpub_date
2016-01-01 00:00:00pages
52-63issue
1eissn
0890-9369issn
1549-5477pii
gad.271130.115journal_volume
30pub_type
杂志文章abstract：:How dividing mammalian cells overcome blocks to DNA replication by DNA damage, depleted nucleotide pools, or template-bound proteins is unclear. Here, we show that the response to blocked replication requires BRCA2, a suppressor of human breast cancer. By using two-dimensional gel electrophoresis, we demonstrate that ...
journal_title：Genes & development
pub_type： 杂志文章
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journal_title：Genes & development
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doi：
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journal_title：Genes & development
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journal_title：Genes & development
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