FOXO4

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Protein

title: "FOXO4" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["forkhead-transcription-factors", "aging-related-proteins"] description: "Protein" topic_path: "arts/film" source: "https://en.wikipedia.org/wiki/FOXO4" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein ::

Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.

Structure and function

FOXO4 is a member of the forkhead family of transcription factors in O subclass, which is characterized by a winged helix domain used for DNA binding. There are 4 members of the FOXO family, including FOXO1, FOXO3, and FOXO6. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation. Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis. Two of the main upstream regulators of FOXO4 activity are phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB. Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.

Clinical significance

Associations with longevity

FOXO transcription factors have been shown to be the downstream effector molecules of insulin-like growth factor (IGF) signaling pathway. In the absence of insulin, PI3K is inactive, so the FOXO homolog daf-16 is able to translocate to the nucleus and turn on many genetic pathways associated with longevity in the roundworm Caenorhabditis elegans. FOXO's activation of these pathways produces an increase in lifespan for worms, flies, mice; similar variants of FOXO3a have been associated with longer human lives as well.

FOXO4 can bind with p53 protein to induce cellular senescence. A peptide competing with FOXO4 can act as a senolytic by excluding p53 from the nucleus.

Cancer

Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation. FOXO4 activates the cell cycle dependent kinase inhibitor, P27, which in turn prevents tumors from progressing into G1. In HER-2 positive tumor cells, increasing FOXO4 activity reduces tumor size. Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia. The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.

In gastric cancers (GC), it has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ. When compared to normal tissue, all GC epithelia had lower levels of FOXO4 located in the nucleus, consistent with less FOXO4 effector activity and FOXO4's function as a suppressor of carcinogenic properties. It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis by downregulating vimentin. These results are consistent with FOXO4 providing a role in inhibiting the epithelia to mesenchymal transition (EMT).

In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4. As with gastric cancer, these cancers with the lowest levels of FOXO4 also had the lowest levels of E-cadherin and highest levels of vimentin, consistent with FOXO4 acting as a suppressor of the EMT phenotype.

Interactions

PIN1, Mdm2 – FOXO4 has been shown to interact with PIN1 and Mdm2.
CIC – chromosomal translocation resulting in a fusion CIC-FOXO4 protein is observed in some tumors.

References

(Feb 1995). "Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family". Genes Chromosomes Cancer.
"FOXO4 forkhead box O4 [ Homo sapiens (human) ]".
(Nov 1990). "The fork head domain: a novel DNA binding motif of eukaryotic transcription factors?". Cell.
(Jan 2000). "Unified nomenclature for the winged helix/forkhead transcription factors". Genes & Development.
(Jun 2007). "Stressing the role of FoxO proteins in lifespan and disease". Nature Reviews Molecular Cell Biology.
(Nov 2005). "FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling". The Biochemical Journal.
(Aug 2005). "Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation". Proceedings of the National Academy of Sciences of the United States of America.
(Mar 2007). "Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding". The Journal of Biological Chemistry.
(2007). "Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification". Nucleic Acids Research.
(Sep 2008). "Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification". Structure.
(Jun 2007). "AKT/PKB signaling: navigating downstream". Cell.
(Apr 2008). "The FoxO code". Oncogene.
(Oct 2008). "SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans". Genes & Development.
(Dec 1993). "A C. elegans mutant that lives twice as long as wild type". Nature.
(Sep 2008). "FOXO3A genotype is strongly associated with human longevity". Proceedings of the National Academy of Sciences of the United States of America.
(2017). "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging". [[Cell (journal).
(Mar 1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science.
(Apr 2004). "High frequency of mutations of the PIK3CA gene in human cancers". Science.
(Apr 2005). "PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma". Cancer Research.
(Mar 2005). "Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity". Oncogene.
(Jan 2007). "FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis". Cell.
(Dec 2011). "MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4". Carcinogenesis.
(2014). "The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer". BMC Cancer.
(2014). "Low expression of the FoxO4 gene may contribute to the phenomenon of EMT in non-small cell lung cancer". Asian Pacific Journal of Cancer Prevention.
(Sep 2008). "The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors". Cancer Res..
(2008). "Mdm2 induces mono-ubiquitination of FOXO4". PLOS ONE.
(April 2020). "Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor". The Journal of Pathology.

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