FOXO3

Forkhead box O3, also known as FOXO3 or FOXO3a, is a human is_associated_with::protein encoded by the FOXO3 is_associated_with::gene.

Function
FOXO3 belongs to the O subclass of the forkhead family of is_associated_with::transcription factors which are characterized by a distinct fork head is_associated_with::DNA-binding domain. There are three other FoxO family members in humans, FOXO1, FOXO4 and FOXO6. These transcription factors share the ability to be inhibited and translocated out of the nucleus on is_associated_with::phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway (aside from FOXO6, which may be constitutively nuclear). Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.

This protein likely functions as a trigger for is_associated_with::apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA, or downregulation of anti-apoptotic proteins such as FLIP.

Gopinath et al.(2014) demonstrate a functional requirement for FOXO3 as a regulator of is_associated_with::Notch signaling pathway (an essential regulator of quiescence in is_associated_with::adult stem cells) in the self-renewal of stem cells during is_associated_with::muscle regeneration.

It is thought that FOXO3a is also involved in protection from oxidative stress by upregulating antioxidants such as is_associated_with::catalase and is_associated_with::MnSOD. is_associated_with::Ron DePinho's group generated Foxo3 knockout mice, and showed that female exhibit a dramatic age-dependent infertility, due to premature ovarian failure.

Clinical significance
Deregulation of FOXO3a is involved in tumorigenesis, for example translocation of this gene with the MLL gene is associated with secondary acute is_associated_with::leukemia. Downregulation of FOXO3a activity is often seen in cancer (e.g. by increase in Akt activity resulting from loss of PTEN). FOXO3 is known as a tumour suppressor.

Alternatively spliced transcript variants encoding the same protein have been observed.

Association with longevity
A variant of FOXO3 has been shown to be associated with is_associated_with::longevity in humans. It is found in most is_associated_with::centenarians across a variety of ethnic groups around the world. The homologous genes is_associated_with::daf-16 in the is_associated_with::nematode C. elegans and is_associated_with::dFOXO in the fruit fly are also associated with longevity in those organisms.