FEATURES

DESCRIPTION

Also known as FOXO1_HUMAN, FOXO1, FKHR, FOXO1A. Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress (PubMed:10358076, PubMed:12228231, PubMed:15220471, PubMed:15890677, PubMed:18356527, PubMed:19221179, PubMed:20543840, PubMed:21245099). Binds to the insulin response element (IRE) with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3' (PubMed:10358076). Activity suppressed by insulin (PubMed:10358076). Main regulator of redox balance and osteoblast numbers and controls bone mass (By similarity). Orchestrates the endocrine function of the skeleton in regulating glucose metabolism (By similarity). Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity). Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity (By similarity). Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP (By similarity). In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and PCK1 (By similarity). Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1 (PubMed:18356527, PubMed:19221179). Promotes neural cell death (PubMed:18356527). Mediates insulin action on adipose tissue (By similarity). Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake (By similarity). Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells (By similarity). Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner (PubMed:20543840). Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling (By similarity). Regulates endothelial cell (EC) viability and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis (PubMed:31063815). Interacts with LRPPRC. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-256 leading to its nuclear import. Interacts (acetylated form) with PPARG. Interacts with XBP1 isoform 2; this interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway (By similarity). Interacts with NLK. Interacts with SIRT1; the interaction results in the deacetylation of FOXO1 leading to activation of FOXO1-mediated transcription of genes involved in DNA repair and stress resistance. Binds to CDK1. Interacts with the 14-3-3 proteins, YWHAG and YWHAZ; the interactions require insulin-stimulated phosphorylation on Thr-24, promote nuclear exit and loss of transcriptional activity. Interacts with SKP2; the interaction ubiquitinates FOXO1 leading to its proteosomal degradation. The interaction requires the presence of KRIT1. Interacts (via the C-terminal half) with ATF4 (via its DNA-binding domain); the interaction occurs in osteoblasts, regulates glucose homeostasis via suppression of beta-cell proliferation and subsequent decrease in insulin production. Interacts with PRMT1; the interaction methylates FOXO1, prevents PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus. Interacts with EP300 and CREBBP; the interactions acetylate FOXO1. Interacts with SIRT2; the interaction is disrupted in response to oxidative stress or serum deprivation, leading to increased level of acetylated FOXO1, which promotes stress-induced autophagy by stimulating E1-like activating enzyme ATG7. Interacts (acetylated form) with ATG7; the interaction is increased in response to oxidative stress or serum deprivation and promotes the autophagic process leading to cell death. Interacts (via the Fork-head domain) with CEBPA; the interaction increases when FOXO1 is deacetylated. Interacts with WDFY2. Forms a complex with WDFY2 and AKT1 (By similarity). Interacts with CRY1 (By similarity). Interacts with PPIA/CYPA; the interaction promotes FOXO1 dephosphorylation, nuclear accumulation and transcriptional activity (PubMed:31063815).

EXTERNAL LINKS

FOXO1

Mutations

Mutation(s) distribution

Mutations table