气候变化领域集成服务门户(CCPortal): Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors

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DOI	10.1073/pnas.2020152118
	Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors
	Helfinger V.; Von Gall F.F.; Henke N.; Kunze M.M.; Schmid T.; Rezende F.; Heidler J.; Wittig I.; Radeke H.H.; Marschall V.; Anderson K.; Shah A.M.; Fulda S.; Brune B.; Brandes R.P.; Schroder K.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Reactive oxygen species (ROS) can cause cellular damage and promote cancer development. Besides such harmful consequences of overproduction of ROS, all cells utilize ROS for signaling purposes and stabilization of cell homeostasis. In particular, the latter is supported by the NADPH oxidase 4 (Nox4) that constitutively produces low amounts of H2O2. By that mechanism, Nox4 forces differentiation of cells and prevents inflammation. We hypothesize a constitutive low level of H2O2maintains basal activity of cellular surveillance systems and is unlikely to be cancerogenic. Utilizing two different murine models of cancerogen-induced solid tumors, we found that deletion of Nox4 promotes tumor formation and lowers recognition of DNA damage. Nox4 supports phosphorylation of H2AX (γH2AX), a prerequisite of DNA damage recognition, by retaining a sufficiently low abundance of the phosphatase PP2A in the nucleus. The underlying mechanism is continuous oxidation of AKT by Nox4. Interaction of oxidized AKT and PP2A captures the phosphatase in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of γH2AX. Simultaneously AKT is left phosphorylated. Thus, in the absence of Nox4, DNA damage is not recognized and the increased activity of AKT supports proliferation. The combination of both events results in genomic instability and promotes tumor formation. By identifying Nox4 as a protective source of ROS in cancerogeninduced cancer, we provide a piece of knowledge for understanding the role of moderate production of ROS in preventing the initiation of malignancies. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	AKT; Genomic instability; Nox4; Solid tumors
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180291
作者单位	Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, 60590, Germany; Institute for Biochemistry I/ Pathobiochemistry, Goethe University, Frankfurt am Main, 60590, Germany; Functional Proteomics, SFB 815 Core Unit, Goethe University, Frankfurt am Main, 60590, Germany; Cluster of Excellence 'Macromolecular Complexes' Goethe University, Frankfurt am Main, 60590, Germany; Pharmazentrum Frankfurt, Goethe University, Frankfurt am Main, 60590, Germany; Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt am Main, 60590, Germany; Signaling Department, The Babraham Institute, Cambridge, CB22 3AT, United Kingdom; Cardiovascular Division, King's College London British Heart Foundation Centre, London, WC2R 2LS, United Kingdom
推荐引用方式 GB/T 7714	Helfinger V.,Von Gall F.F.,Henke N.,et al. Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors[J],2021,118(11).
APA	Helfinger V..,Von Gall F.F..,Henke N..,Kunze M.M..,Schmid T..,...&Schroder K..(2021).Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Helfinger V.,et al."Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).