Triple Layer Control: Phosphorylation, Acetylation and Ubiquitination of FOXO Proteins

来自 Taylor & Francis

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115

作者：

PK Vogt，H Jiang，M Aoki

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摘要：

FOXO proteins are transcriptional regulators that control cell cycle progression, DNA repair, apoptosis, and defense against oxidative damage. These divergent functions of FOXO proteins are regulated by signal-induced, post-translational modifications. Phosphorylation of cytoplasmic FOXO at specific sites by JNK initiates translocation into the nucleus. Acetylation and deacetylation of nuclear FOXO affects the selection of transcriptional programs that are controlled by FOXO proteins. Activation of Akt by growth factors results in phosphorylation of nuclear FOXO at specific sites followed by additional phosphorylations mediated by other kinases. Akt-dependent phosphorylation reduces the DNA-binding activity of FOXO, interferes with binding to the co-activators p300/CBP, and inactivates the FOXO nuclear translocation signal. The Akt-phosphorylated FOXO is exported from the nucleus in a CRM1- and 14-3-3-dependent process. Cytoplasmic, Akt-phosphorylated FOXO interacts with the ubiquitin ligase Skp2 and is targeted for proteasomal degradation. The nuclear-cytoplasmic FOXO shuttle is driven by stress signals that result in nuclear import and FOXO transcriptional activity and growth signals that initiate nuclear export and proteasomal degradation of FOXO.

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关键词：

FOXO phosphorylation acetylation ubiquitination Akt JNK SIRT1 Skp2