InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: FOXO1

Summary

InnateDB Protein

IDBP-26477.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

FOXO1

Protein Name

forkhead box O1

Synonyms

FKH1; FKHR; FOXO1A;

Species

Homo sapiens

Ensembl Protein

ENSP00000368880

InnateDB Gene

IDBG-26475 (FOXO1)

Protein Structure

UniProt Annotation

Function

Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress. 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'. Activity suppressed by insulin. Main regulator of redox balance and osteoblast numbers and controls bone mass. Orchestrates the endocrine function of the skeleton in regulating glucose metabolism. Acts syngernistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity. Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP. In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A to activate the expression of genes such as IGFBP1, G6PC and PPCK1. Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and SKT4/MST1. Promotes neural cell death. Mediates insulin action on adipose. 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. Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells. Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner. {ECO:0000269PubMed:10358076, ECO:0000269PubMed:12228231, ECO:0000269PubMed:15220471, ECO:0000269PubMed:15890677, ECO:0000269PubMed:18356527, ECO:0000269PubMed:19221179, ECO:0000269PubMed:20543840, ECO:0000269PubMed:21245099}.

Subcellular Localization

Cytoplasm. Nucleus. Note=Shuttles between the cytoplasm and nucleus. Largely nuclear in unstimulated cells. In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus (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. Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes nuclear accumulation. Phosphorylation by NLK results in nuclear export. Translocates to the nucleus upon oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1. SGK1-mediated phosphorylation also results in nuclear translocation. Retained in the nucleus under stress stimuli including oxidative stress, nutrient deprivation or nitric oxide. Retained in the nucleus on methylation. {ECO:0000250}.

Disease Associations

Rhabdomyosarcoma 2 (RMS2) [MIM:268220]: 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. Note=The gene represented in this entry may be involved in disease pathogenesis. Chromosomal aberrations involving FOXO1 are found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with PAX3 and translocation t(1;13)(p36;q14) with PAX7. The resulting protein is a transcriptional activator.

Tissue Specificity

Ubiquitous. {ECO:0000269PubMed:9479491}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 66 experimentally validated interaction(s) in this database.
They are also associated with 12 interaction(s) predicted by orthology.

Experimentally validated
Total	66 [view]
Protein-Protein	62 [view]
Protein-DNA	4 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	12 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000989	transcription factor binding transcription factor activity
GO:0001078	RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription
GO:0003677	DNA binding
GO:0003682	chromatin binding
GO:0003700	sequence-specific DNA binding transcription factor activity
GO:0005515	protein binding
GO:0031625	ubiquitin protein ligase binding
GO:0043565	sequence-specific DNA binding
GO:0051721	protein phosphatase 2A binding

Biological Process

GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0001568	blood vessel development
GO:0001659	temperature homeostasis
GO:0001678	cellular glucose homeostasis
GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0006357	regulation of transcription from RNA polymerase II promoter
GO:0006473	protein acetylation
GO:0006915	apoptotic process
GO:0006974	cellular response to DNA damage stimulus
GO:0007173	epidermal growth factor receptor signaling pathway
GO:0008286	insulin receptor signaling pathway
GO:0008543	fibroblast growth factor receptor signaling pathway
GO:0009267	cellular response to starvation
GO:0010508	positive regulation of autophagy
GO:0031018	endocrine pancreas development
GO:0032869	cellular response to insulin stimulus
GO:0032873	negative regulation of stress-activated MAPK cascade
GO:0034599	cellular response to oxidative stress
GO:0035947	regulation of gluconeogenesis by regulation of transcription from RNA polymerase II promoter
GO:0038095	Fc-epsilon receptor signaling pathway
GO:0042127	regulation of cell proliferation
GO:0042593	glucose homeostasis
GO:0043065	positive regulation of apoptotic process
GO:0043066	negative regulation of apoptotic process
GO:0045087	innate immune response
GO:0045444	fat cell differentiation
GO:0045599	negative regulation of fat cell differentiation
GO:0045722	positive regulation of gluconeogenesis
GO:0045732	positive regulation of protein catabolic process
GO:0045892	negative regulation of transcription, DNA-templated
GO:0045893	positive regulation of transcription, DNA-templated
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0048015	phosphatidylinositol-mediated signaling
GO:0070417	cellular response to cold
GO:0071455	cellular response to hyperoxia
GO:0071732	cellular response to nitric oxide
GO:2000505	regulation of energy homeostasis