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Merck
  • Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors.

Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors.

Proceedings of the National Academy of Sciences of the United States of America (2021-04-11)
Valeska Helfinger, Florian Freiherr von Gall, Nina Henke, Michael M Kunze, Tobias Schmid, Flavia Rezende, Juliana Heidler, Ilka Wittig, Heinfried H Radeke, Viola Marschall, Karen Anderson, Ajay M Shah, Simone Fulda, Bernhard Brüne, Ralf P Brandes, Katrin Schröder
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 H2O2 maintains 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 cancerogen-induced cancer, we provide a piece of knowledge for understanding the role of moderate production of ROS in preventing the initiation of malignancies.

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胰蛋白酶-EDTA 溶液, 1 ×, sterile; sterile-filtered, BioReagent, suitable for cell culture, 0.5 g porcine trypsin and 0.2 g EDTA, 4Na per liter of Hanks′ Balanced Salt Solution with phenol red
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抗磷酸组蛋白H3(Ser10)抗体,有丝分裂标记, Upstate®, from rabbit
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