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Cell survival and growth are also promoted by AKT phosphorylation of Forkhead box (FOX) transcription factors, most notably FoxO1, FoxO3a and FoxO4. Once phosphorylated by AKT, these factors are removed from the nucleus, associate with 14-3-3 proteins, and are retained in the cytoplasm, thus producing a change in their transcriptional activity. For instance, unphosphorylated FoxO3a in the nucleus triggers apoptosis, most likely by inducing the expression of critical genes, such as the Fas ligand gene. In another example, AKT phosphorylation of FOXO4 prevents FOXO4-mediated upregulation of p27Kip1.
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