Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene. [5]
Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene. [5]
FOXO3 belongs to the O subclass of the forkhead family of transcription factors 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 signaling pathway (aside from FOXO6, which may be constitutively nuclear). [6] Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.
The use of FOXO3a knockout mice has revealed a diverse range of functions in both health and disease, namely infertility, lymphoproliferation, adenoma, organ inflammation, metabolism etc.; yet despite the purported importance of FOXO transcription factors in aging, FOXO3A knockout mice do not show an obvious shortening of lifespan or accelerated aging [7]
Yu & Fellows et al. (2018) demonstrated that FOXO3a activation in vascular smooth muscle cells induces prominent apoptosis and extracellular matrix breakdown in vitro and exacerbates atherosclerosis and vascular remodelling in vivo. Also, these processes were at least partially dependent on MMP-13, as shown by siRNA knockdown and specific pharmacological inhibition. Further experiments also revealed MMP-13 as a novel, bona fide transcriptional target gene of FOXO3a in VSMCs. [8]
FOXO3a also functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA , [9] or downregulation of anti-apoptotic proteins such as FLIP. [10]
Gopinath et al. (2014) [11] demonstrate a functional requirement for FOXO3 as a regulator of Notch signaling pathway (an essential regulator of quiescence in adult stem cells) in the self-renewal of stem cells during muscle regeneration.
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.
Deregulation of FOXO3a is involved in tumorigenesis, [12] 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 (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. [13]
The ketone body β-hydroxybutyrate has been shown in mice to increase gene expression of FOXO3a by histone deacetylase inhibition, upon which FOXO3a transcriptionally increased gene expression of the antioxidant enzymes SOD2 and catalase. [14] Plasma levels of β-hydroxybutyrate increase with fasting or a ketogenic diet. [15]
Genetic variation in FOXO3 has been shown to be associated with healthspan and longevity in humans. [16] It is found in most centenarians across a variety of ethnic groups around the world. [17] [18] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms. [19] Mice lacking FOXO3 do not show obvious accelerated aging or shortened lifespan.
In a meta-analysis of 78,308 individuals of European descent, a particular single nucleotide polymorphism (SNP) (rs2490272) in an intronic region of FOXO3 and neighboring SNPs in the promoter region, had the strongest associations with intelligence. [20] Various types of tests had been used to measure intelligence.
FOXproteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic development. FOX proteins also have pioneering transcription activity by being able to bind condensed chromatin during cell differentiation processes.
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases.
The nuclear receptor 4A1 also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the NR4A1 gene.
Forkhead box protein P1 is a protein that in humans is encoded by the FOXP1 gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX family of transcription factors.
Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.
Activating transcription factor 4 , also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.
Bcl-2-like protein 11, commonly called BIM, is a protein that in humans is encoded by the BCL2L11 gene.
DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.
Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.
Krueppel-like factor 10 is a protein that in humans is encoded by the KLF10 gene.
Forkhead box protein E1 is a protein that in humans is encoded by the FOXE1 gene.
Forkhead box protein H1 is a protein that in humans is encoded by the FOXH1 gene.
E3 ubiquitin-protein ligase TRIM63, also known as "MuRF1", is an enzyme that in humans is encoded by the TRIM63 gene.
Angiogenic factor with G patch and FHA domains 1 is a protein that in humans is encoded by the AGGF1 gene.
Forkhead box protein K1 is a transcription factor of the forkhead box family that in humans is encoded by the FOXK1 gene.
The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.
Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.
DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans. It is responsible for activating genes involved in longevity, lipogenesis, heat shock survival and oxidative stress responses. It also protects C.elegans during food deprivation, causing it to transform into a hibernation - like state, known as a Dauer. DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor DAF-2. The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism.
Ovarian follicle activation can be defined as primordial follicles in the ovary moving from a quiescent (inactive) to a growing phase. The primordial follicle in the ovary is what makes up the “pool” of follicles that will be induced to enter growth and developmental changes that change them into pre-ovulatory follicles, ready to be released during ovulation. The process of development from a primordial follicle to a pre-ovulatory follicle is called folliculogenesis.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.