FOXO1

This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma. [provided by RefSeq, Jul 2008]

Forkhead Box O1

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).

Apoptotic process Source: UniProtKB
Autophagy Source: UniProtKB-KW
Cellular glucose homeostasis Source: UniProtKB
Cellular response to cold Source: UniProtKB
Cellular response to dexamethasone stimulus Source: Ensembl
Cellular response to DNA damage stimulus Source: UniProtKB
Cellular response to hydrogen peroxide Source: Ensembl
Cellular response to hyperoxia Source: UniProtKB
Cellular response to insulin stimulus Source: UniProtKB
Cellular response to nitric oxide Source: UniProtKB
Cellular response to oxidative stress Source: UniProtKB
Cellular response to starvation Source: UniProtKB
Enamel mineralization Source: Ensembl
Energy homeostasis Source: UniProtKB
Fat cell differentiation Source: UniProtKB
Insulin receptor signaling pathway Source: UniProtKB
Negative regulation of apoptotic process Source: UniProtKB
Negative regulation of cardiac muscle hypertrophy in response to stress Source: UniProtKB
Negative regulation of fat cell differentiation Source: UniProtKB
Negative regulation of stress-activated MAPK cascade Source: BHF-UCL
Negative regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of apoptotic process Source: UniProtKB
Positive regulation of autophagy Source: UniProtKB
Positive regulation of protein catabolic process Source: UniProtKB
Positive regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Protein acetylation Source: UniProtKB
Regulation of transcription by RNA polymerase II Source: GO_Central
Response to fatty acid Source: UniProtKB
Response to fluoride Source: Ensembl
Temperature homeostasis Source: UniProtKB

Nucleus; Cytoplasm. Shuttles between the cytoplasm and nucleus. Largely nuclear in unstimulated cells (PubMed:11311120, PubMed:12228231, PubMed:19221179, PubMed:21245099, PubMed:20543840). In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus (By similarity). Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (By similarity). Insulin-induced phosphorylation at Ser-256 by PKB/AKT1 leads, via stimulation of Thr-24 phosphorylation, to binding of 14-3-3 proteins and nuclear export to the cytoplasm where it is degraded by the ubiquitin-proteosomal pathway (PubMed:11237865, PubMed:12228231). Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes nuclear accumulation (PubMed:18356527). Phosphorylation by NLK results in nuclear export (By similarity). Translocates to the nucleus upon oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1 (PubMed:19221179, PubMed:21245099). SGK1-mediated phosphorylation also results in nuclear translocation (By similarity). Retained in the nucleus under stress stimuli including oxidative stress, nutrient deprivation or nitric oxide (By similarity). Retained in the nucleus on methylation (By similarity). PPIA/CYPA stimulates its nuclear accumulation (PubMed:31063815).

Rhabdomyosarcoma 2 (RMS2):
A form of rhabdomyosarcoma, a highly malignant tumor of striated muscle derived from primitive mesenchymal cells and exhibiting differentiation along rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently occurring soft tissue sarcomas and the most common in children. It occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal rhabdomyosarcomas.

Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-256 and Ser-322 by PKB/AKT1 promotes nuclear export and inactivation of transactivational activity. Phosphorylation on Thr-24 is required for binding 14-3-3 proteins. Phosphorylation of Ser-256 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-319, permitting phosphorylation of Ser-322 and Ser-325, probably by CDK1, leading to nuclear exclusion and loss of function. Stress signals, such as response to oxygen or nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading to nuclear retention. Phosphorylation of Ser-329 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-256 by PP2A in beta-cells under oxidative stress leading to nuclear retention (By similarity). Phosphorylation of Ser-249 by CDK1 disrupts binding of 14-3-3 proteins leading to nuclear accumulation and has no effect on DNA-binding nor transcriptional activity. Phosphorylation by STK4/MST1 on Ser-212, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export. PPIA/CYPA promotes its dephosphorylation on Ser-256 (PubMed:31063815).
Acetylated. Acetylation at Lys-262, Lys-265 and Lys-274 are necessary for autophagic cell death induction. Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death.
Ubiquitinated by SKP2. Ubiquitination leads to proteasomal degradation.
Methylation inhibits AKT1-mediated phosphorylation at Ser-256 and is increased by oxidative stress.
Once in the nucleus, acetylated by CREBBP/EP300. Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-256. Deacetylation by SIRT1 results in reactivation of the transcriptional activity. Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation. By contrast, resveratrol acts independently of acetylation.