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ROS ‐generating oxidases N ox1 and N ox4 contribute to oncogenic R as‐induced premature senescence
Author(s) -
Kodama Ryo,
Kato Masayoshi,
Furuta Shuichi,
Ueno Shouta,
Zhang Yugen,
Matsuno Kuniharu,
YabeNishimura Chihiro,
Tanaka Eiji,
Kamata Tohru
Publication year - 2013
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12015
Subject(s) - nox1 , biology , nox4 , microbiology and biotechnology , small interfering rna , senescence , nadph oxidase , reactive oxygen species , gene silencing , signal transduction , dna damage , transfection , cell culture , biochemistry , genetics , gene , dna
Activated oncogenes induce premature cellular senescence, a permanent state of proliferative arrest in primary rodent and human fibroblasts. Recent studies suggest that generation of reactive oxygen species ( ROS ) is involved in oncogenic R as‐induced premature senescence. However, the signaling mechanism controlling this oxidant‐mediated irreversible growth arrest is not fully understood. Here, we show that through the R as/ MEK pathway, R as oncogene up‐regulated the expression of superoxide‐generating oxidases, N ox1 in rat REF 52 cells and N ox4 in primary human lung TIG ‐3 cells, leading to an increase in intracellular level of ROS . Ablation of N ox1 and N ox4 by small interfering RNA s (si RNA s) blocked the R as V 12 senescent phenotype including β‐galactosidase activity, growth arrest and accumulation of tumor suppressors such as p53 and p16 Ink4a . This suggests that N ox‐generated ROS transduce senescence signals by activating the p53 and p16 Ink4a pathway. Furthermore, N ox1 and N ox4 si RNA s inhibited both R as‐induced DNA damage response and p38 MAPK activation, whereas overexpression of N ox1 and N ox4 alone was able to induce senescence. The involvement of N ox1 in R as‐induced senescence was also confirmed with embryonic fibroblasts derived from N ox1 knockout mice. Together, these findings suggest that N ox1‐ and N ox4‐generated ROS play an important role in R as‐induced premature senescence, which may involve DNA damage response and p38 MAPK signaling pathways.