Phosphorylation and acetylation modifications of FOXO3a: Independently or synergistically?

Abstract

Forkhead box class O 3a (FOXO3a) is a transcription factor that has emerged as being a tumor suppressor and longevity factor. The precise regulation of FOXO3a transactivation of target genes is achieved via post-translational modifications (PTMs) and specific protein-protein interactions. The multiple types of PTMs that FOXO3a undergoes, including phosphorylation, acetylation, methylation and ubiquitination, serve important roles in directing its subcellular localization and transcription activity, which are central to the integration of insulin/growth factor signaling and oxidative/nutrient stress signaling. The present review summarizes the modifications of FOXO3a that occur via phosphorylation and acetylation. In addition, the synergistic effect of multiple phosphorylations on FOXO3a and the crosstalk between phosphorylation and acetylation in the regulation of FOXO3a are discussed. These discussions may highlight potential strategies for the prevention of cancer and aging.

Analysis of Fox genes inSchmidtea mediterraneareveals new families and a conserved role ofSmed-foxOin controlling cell death

“…genes related to developmental processes, such as cell death, DNA repair and cell cycle (41). In good nutrient conditions, AKT phosphorylates three specific sites in Smed-FoxO (55,56), which leads to its ubiquitin degradation thanks to the 14-3-3…”

“…FoxO also has a conserved role in maintaining cellular energy homeostasis by coordinating cellular supplies and demands (39). When nutrients are available, InsulinR is activated and FoxO is phosphorylated by AKT, which inhibits its entrance into the nucleus (55,56,71). Under conditions of growth factor limitation or other stresses, FoxO enters the nucleus and inhibits mTORC1.…”

Molecular Imaging of Sirtuin1 Expression–Activity in Rat Brain Using Positron-Emission Tomography–Magnetic-Resonance Imaging with [18F]-2-Fluorobenzoylaminohexanoicanilide

“…38b Within the nucleus accumbens (Acb), SIRT1 was shown to deacetylate FOXO3a and to increase the expression of several target genes that enhance cocaine-addiction behaviors. 49 Furthermore, chronic cocaine usage has been demonstrated to increase SIRT1 activity within the Acb and SIRT1-mRNA production through an increase in the acetylation of the gene promoter for SIRT1 transcription. 50 Therefore, PET imaging of SIRT1 expression−activity with 2-[ 18 F]BzAHA may advance our understanding of mechanisms of addiction and aid in the development of new therapies for addictive disorders.…”

Water Extract of Lotus Leaf Alleviates Dexamethasone-Induced Muscle Atrophy via Regulating Protein Metabolism-Related Pathways in Mice

“…The gene expressions of atrogin-1 and MuRF1 are regulated by forkhead box O (FoxO), a transcriptional factor that is abundantly present in muscle [ 9 , 10 ]. Activation of FoxO is determined by two mechanisms: cytosol-nuclear shuttling and transcriptional activity [ 11 ]. These mechanisms are positively or negatively controlled by phosphorylation, depending on the upstream kinase and phosphor-accepting sites.…”