PTEN deletion leads to deregulation of antioxidants and increased oxidative damage in mouse embryonic fibroblasts.
Despite the significance of oxidative damage in carcinogenesis, the molecular mechanisms that lead to increased susceptibility to oxidative stress are not well understood. We now report a link between loss of protection against oxidative damage and loss of function of PTEN, a highly mutated tumor suppressor gene in a variety of human tumors. Using two-dimensional gel electrophoresis, combined with Western and Northern blot analyses, we found that PTEN deficiency in mouse embryonic fibroblasts (MEFs) displays deregulated expression of several antioxidant enzymes, including peroxiredoxins 1, 2, 5, and 6 and Cu, Zn superoxide dismutase. In these Pten-deleted MEFs, the basal levels of reactive oxygen species (ROS) were increased, and both the basal level and the ROS-induced oxidative damage of DNA were increased, as evidenced by increased levels of hydrogen peroxide (H2O2), superoxide anion, 8-hydroxy-2'-deoxyguanosine, and DNA double-strand breaks. We further show that Pten deletion is correlated with resistance to H2O2-induced expression of several antioxidants. These findings suggest an essential role for PTEN in maintaining the normal redox state of mouse embryonic fibroblasts against oxidative damage. They also provide a molecular link between PTEN, whose inactivation is known to be involved in a variety of human tumors, and antioxidants, whose perturbation leads to oxidative damage of cells.
Huo
Yan-Ying
YY
Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China. yanying_huo@yahoo.com.cn
Li
Gang
G
Duan
Rui-Feng
RF
Gou
Qiao
Q
Fu
Chun-Ling
CL
Hu
Ying-Chun
YC
Song
Bo-Qiang
BQ
Yang
Zhi-Hua
ZH
Wu
De-Chang
DC
Zhou
Ping-Kun
PK
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D013482:Superoxide Dismutase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse