FOXO4

This gene encodes a member of the O class of winged helix/forkhead transcription factor family. Proteins encoded by this class are regulated by factors involved in growth and differentiation indicating they play a role in these processes. A translocation involving this gene on chromosome X and the homolog of the Drosophila trithorax gene, encoding a DNA binding protein, located on chromosome 11 is associated with leukemia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

Full Name

Forkhead Box O4

Function

Transcription factor involved in the regulation of the insulin signaling pathway. Binds to insulin-response elements (IREs) and can activate transcription of IGFBP1. Down-regulates expression of HIF1A and suppresses hypoxia-induced transcriptional activation of HIF1A-modulated genes. Also involved in negative regulation of the cell cycle. Involved in increased proteasome activity in embryonic stem cells (ESCs) by activating expression of PSMD11 in ESCs, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity.

Biological Process

Aging Source: Ensembl
Insulin receptor signaling pathway Source: UniProtKB
Mitotic G2 DNA damage checkpoint signaling Source: Ensembl
Muscle organ development Source: UniProtKB-KW
Negative regulation of angiogenesis Source: UniProtKB
Negative regulation of cell population proliferation Source: UniProtKB
Negative regulation of G0 to G1 transition Source: UniProtKB
Negative regulation of smooth muscle cell differentiation Source: UniProtKB
Positive regulation of smooth muscle cell migration Source: Ensembl
Positive regulation of transcription by RNA polymerase II Source: NTNU_SB
Regulation of cell cycle Source: UniProtKB
Regulation of transcription, DNA-templated Source: UniProtKB
Regulation of transcription by RNA polymerase II Source: GO_Central
Response to nutrient levels Source: Ensembl
Response to water-immersion restraint stress Source: Ensembl
Stem cell differentiation Source: UniProtKB

Cellular Location

Cytoplasm; Nucleus. When phosphorylated, translocated from nucleus to cytoplasm. Dephosphorylation triggers nuclear translocation. Monoubiquitination increases nuclear localization. When deubiquitinated, translocated from nucleus to cytoplasm.

Involvement in disease

A chromosomal aberration involving FOXO4 is found in acute leukemias. Translocation t(X;11)(q13;q23) with KMT2A/MLL1. The result is a rogue activator protein.

PTM

Acetylation by CREBBP/CBP, which is induced by peroxidase stress, inhibits transcriptional activity. Deacetylation by SIRT1 is NAD-dependent and stimulates transcriptional activity.
Phosphorylation by PKB/AKT1 inhibits transcriptional activity and is responsible for cytoplasmic localization. May be phosphorylated at multiple sites by NLK.
Monoubiquitinated; monoubiquitination is induced by oxidative stress and reduced by deacetylase inhibitors; results in its relocalization to the nucleus and its increased transcriptional activity. Deubiquitinated by USP7; deubiquitination is induced by oxidative stress; enhances its interaction with USP7 and consequently, deubiquitination; increases its translocation to the cytoplasm and inhibits its transcriptional activity. Hydrogene-peroxide-induced ubiquitination and USP7-mediated deubiquitination have no major effect on its protein stability.