Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47^phox.

Akt activation up-regulates the intracellular levels of reactive oxygen species by inhibiting scavenging. Of the Akt isoforms, Akt3 has also been shown to up-regulate duanyu1670 by promoting mitochondrial biogenesis. Here, we employ a set of isogenic cell lines that express different Akt isoforms, to show that the most robust inducer of duanyu1670 is Akt3. As a result, Akt3-expressing cells activate the DNA damage response pathway, express high levels of p53 and its direct transcriptional target miR-34, and exhibit a proliferation defect, which is rescued by the antioxidant N-acetylcysteine. The importance of the DNA damage response in the inhibition of cell proliferation by Akt3 was confirmed by Akt3 overexpression in p53 ^-/- and INK4a ^-/-/Arf ^-/- mouse embryonic fibroblasts (MEFs), which failed to inhibit cell proliferation, despite the induction of high levels of The induction of duanyu1670 by Akt3 is due to the phosphorylation of the NADPH oxidase subunit p47^phox, which results in NADPH oxidase activation. Expression of Akt3 in p47 ^-/- MEFs failed to induce duanyu1670 and to inhibit cell proliferation. Notably, the proliferation defect was rescued by wild-type p47^phox, but not by the phosphorylation site mutant of p47^phox In agreement with these observations, Akt3 up-regulates p53 in human cancer cell lines, and the expression of Akt3 positively correlates with the levels of p53 in a variety of human tumors. More important, Akt3 alterations correlate with a higher frequency of mutation of p53, suggesting that tumor cells may adapt to high levels of Akt3, by inactivating the DNA damage response.

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