FOXO3A
Encyclopedia
Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein
encoded by the FOXO3 gene
.
family of transcription factor
s which are characterized by a distinct fork head 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 phosphorylation
by proteins such as Akt/PKB
in the PI3K
signalling 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 apoptosis
through upregulation of genes
necessary for cell death, such as Bim
and PUMA
, or downregulation of anti-apoptotic proteins such as FLIP
.
It is thought that FOXO3a is also involved in protection from oxidative stress by upregulating antioxidants such as catalase
and MnSOD. Ron DePinho's group generated Foxo3 knockout mice, and showed that female exhibit a dramatic age-dependent infertility, due to premature ovarian failure.
, for example translocation of this gene with the MLL
gene is associated with secondary acute leukemia
. Downregulation of FOXO3a activity is often seen in cancer (eg 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.
in humans. It is found in most centenarians across a variety of ethnic groups around the world. The homologous genes Daf-16
in the nematode
C. elegans
and dFOXO in the fruit fly
are also associated with longevity in those organisms.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by the FOXO3 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
FOXO3 belongs to the O subclass of the forkheadFOX proteins
FOX proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity...
family of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s which are characterized by a distinct fork head 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 phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
by proteins such as Akt/PKB
Akt/PKB signaling pathway
The Akt/PKB signaling pathway is a pathway in cell signaling.Proteins involved include AKT and phosphoinositide 3-kinase .It can be associated with cancer....
in the PI3K
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
signalling 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 apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
through upregulation of genes
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
necessary for cell death, such as Bim
BCL2L11
Bcl-2-like protein 11 is a protein that in humans is encoded by the BCL2L11 gene.-Interactions:BCL2L11 has been shown to interact with DYNLL1, MCL1, BCL2-like 1, BCL2L2 and Bcl-2.-Further reading:...
and PUMA
P53 upregulated modulator of apoptosis
The p53 upregulated modulator of apoptosis also known as Bcl-2-binding component 3 , is a pro-apoptotic protein, member of the Bcl-2 protein family. In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene....
, or downregulation of anti-apoptotic proteins such as FLIP
CFLAR
CASP8 and FADD-like apoptosis regulator is a protein that in humans is encoded by the CFLAR gene. Also called FLICE-like inhibitory protein .-Further reading:...
.
It is thought that FOXO3a is also involved in protection from oxidative stress by upregulating antioxidants such as catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...
and MnSOD. 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 tumorigenesisCarcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
, for example translocation of this gene with the MLL
MLL (gene)
Histone-lysine N-methyltransferase HRX is an enzyme that in humans is encoded by the MLL gene.MLL is a histone methyltransferase deemed a positive global regulator of gene transcription...
gene is associated with secondary acute leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
. Downregulation of FOXO3a activity is often seen in cancer (eg by increase in Akt activity resulting from loss of PTEN
PTEN
PTEN may mean:* Patterson-UTI Energy, Inc., which trades on the NASDAQ stock market under the symbol 'PTEN'* Prime Time Entertainment Network* PTEN , a human tumour suppressor gene on chromosome 10...
). 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 longevityLongevity
The word "longevity" is sometimes used as a synonym for "life expectancy" in demography or known as "long life", especially when it concerns someone or something lasting longer than expected ....
in humans. It is found in most centenarians across a variety of ethnic groups around the world. The homologous genes Daf-16
Daf-16
DAF-16 is part of a group of genes that drive the biological processes involved in ageing, immunity and responses to physical or environmental stresses...
in the nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
and dFOXO in the fruit fly
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
are also associated with longevity in those organisms.
External links
- http://www.cisreg.ca/cgi-bin/tfe/articles.pl?tfid=443 Transcription Factor encyclopedia entry for FOXO3