FOXO3

GeneName

FOXO3

Summary

FOXO3, also known as Foxo3a or FKHRL1, is a 71kDa transcription factor that plays a pivotal role in regulating various cellular processes including apoptosis, autophagy, and stress resistance. It is expressed in multiple tissues, including the brain and ovaries, and is localised in the nucleus, cytoplasm, and mitochondria. FOXO3 binds to DNA and functions as a transcriptional activator or repressor, influencing gene expression in response to various stimuli such as oxidative stress, nutrient availability, and growth factors. Its involvement in the canonical Wnt signalling pathway and cellular responses to stressors highlights its significance in developmental and metabolic processes.

Importance

FOXO3 is relevant to: - Cancer research due to its role in apoptosis and cell cycle regulation, influencing tumour progression and response to therapy - Neurodegenerative diseases as it mediates cellular responses to oxidative stress and amyloid-beta - Ovarian biology, particularly in follicle growth and oocyte maturation, impacting fertility and reproductive health - Metabolic disorders through its regulation of glucose homeostasis and response to starvation

Top Products

For researchers investigating FOXO3, we recommend two excellent primary antibodies that cater to different experimental needs. The first is the well-cited polyclonal antibody, Anti-FOXO3A antibody (ab12162), which has garnered 81 citations and is highly regarded for its performance in immunohistochemistry (IHC) and immunocytochemistry (ICC). This antibody is a trusted choice for those focusing on cellular localisation studies.Additionally, we offer the recombinant monoclonal antibody, Anti-FOXO3A antibody [EPR1950] (ab109629). This product has been validated in knockout models and is suitable for a range of applications, including western blotting (WB) and flow cytometry (FC). With 54 citations, it demonstrates a solid reputation in the research community. The recombinant nature of this antibody ensures batch-to-batch consistency, making it an ideal option for researchers requiring reliable FOXO3 detection across various assays. The Anti-FOXO3A antibody ELISA Kit (ab70314), supported by 3 citations, is an excellent option for researchers looking to measure FOXO3A levels in their samples.

Abcam Product Citation Summary

The data indicates a significant focus on the role of FOXO3 in various human cancer contexts, particularly in studies involving pancreatic cancer, gastric cancer, and breast cancer. Additionally, there are investigations into the effects of treatments such as gilteritinib and PS341 on FOXO3 expression. The use of FOXO3 antibodies in mouse models also highlights its relevance in inflammation and metabolic studies.

Abcam Product Citation Table

Function

Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy (PubMed:10102273, PubMed:16751106, PubMed:21329882, PubMed:30513302). Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins (By similarity). Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (PubMed:10102273, PubMed:16751106). Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription (PubMed:23283301). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. 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). Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3 (PubMed:30513302).

Involvement in disease

A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with KMT2A/MLL1.

Post-translational modifications

In the presence of survival factors such as IGF1, phosphorylated on Thr-32 and Ser-253 by AKT1/PKB (PubMed:10102273). This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm (PubMed:10102273). Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and triggers apoptosis (PubMed:10102273). Although AKT1/PKB doesn't appear to phosphorylate Ser-315 directly, it may activate other kinases that trigger phosphorylation at this residue (PubMed:10102273, PubMed:11154281). Phosphorylated by STK4/MST1 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation (PubMed:16751106). Phosphorylated by PIM1 (PubMed:18593906). Phosphorylation by AMPK leads to the activation of transcriptional activity without affecting subcellular localization (PubMed:17711846). In response to metabolic stress, phosphorylated by AMPK on Ser-30 which mediates FOXO3 mitochondrial translocation (PubMed:29445193). Phosphorylation by MAPKAPK5 promotes nuclear localization and DNA-binding, leading to induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882). Phosphorylated by CHUK/IKKA and IKBKB/IKKB (PubMed:15084260). TNF-induced inactivation of FOXO3 requires its phosphorylation at Ser-644 by IKBKB/IKKB which promotes FOXO3 retention in the cytoplasm, polyubiquitination and ubiquitin-mediated proteasomal degradation (PubMed:15084260). May be dephosphorylated by calcineurin A on Ser-299 which abolishes FOXO3 transcriptional activity (By similarity). In cancer cells, ERK mediated-phosphorylation of Ser-12 is required for mitochondrial translocation of FOXO3 in response to metabolic stress or chemotherapeutic agents (PubMed:29445193). Phosphorylation at Ser-253 promotes its degradation by the proteasome (PubMed:30513302). Dephosphorylation at Ser-253 by protein phosphatase 2A (PPP2CA) promotes its stabilization; interaction with PPP2CA is enhanced by AMBRA1 (PubMed:30513302). Dephosphorylated at Ser-253 by CTDSPL2 (PubMed:28851713).

Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3 with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and proteasomal degradation (PubMed:21841822). Deacetylation by SIRT2 stimulates FOXO3-mediated transcriptional activity in response to oxidative stress (By similarity). Deacetylated by SIRT3 (PubMed:23283301). Deacetylation by SIRT3 stimulates FOXO3-mediated mtDNA transcriptional activity in response to metabolic stress (PubMed:23283301).

Heavily methylated by SET9 which decreases stability, while moderately increasing transcriptional activity. The main methylation site is Lys-271. Methylation doesn't affect subcellular location.

Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation.

The N-terminus is cleaved following import into the mitochondrion.

Tissue Specificity

Ubiquitous.

Cellular localization

• Cytoplasm
• Cytosol
• Nucleus
• Mitochondrion matrix
• Mitochondrion outer membrane
• Peripheral membrane protein
• Cytoplasmic side
• Retention in the cytoplasm contributes to its inactivation (PubMed:10102273, PubMed:15084260, PubMed:16751106). Translocates to the nucleus upon oxidative stress and in the absence of survival factors (PubMed:10102273, PubMed:16751106). Translocates from the cytosol to the nucleus following dephosphorylation in response to autophagy-inducing stimuli (By similarity). Translocates in a AMPK-dependent manner into the mitochondrion in response to metabolic stress (PubMed:23283301, PubMed:29445193). Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (By similarity).

Alternative names

FKHRL1, FOXO3A, FOXO3, Forkhead box protein O3, AF6q21 protein, Forkhead in rhabdomyosarcoma-like 1

Database links

swissprot:O43524 omim:602681 entrezGene:2309

Other research areas

• Oncology