**FOXO3 Function and Regulation**:
– FOXO3 belongs to the O subclass of the forkhead family of transcription factors.
– FOXO3 shares characteristics with FOXO1, FOXO4, and FOXO6.
– FOXO3 can be inhibited and translocated out of the nucleus by proteins like Akt/PKB.
– Post-translational modifications like acetylation and methylation can affect FOXO3a activity.
– FOXO3a knockout mice show diverse functions in health and disease.
– Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
– FOXO proteins regulate tumor necrosis factor-related apoptosis-inducing ligand expression.
– The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP.
– Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases.
– Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells.
**FOXO3 in Apoptosis**:
– FOXO3a activation induces apoptosis in vascular smooth muscle cells.
– FOXO3a exacerbates atherosclerosis and vascular remodeling.
– MMP-13 is a transcriptional target gene of FOXO3a in VSMCs.
– FOXO3a triggers apoptosis by regulating genes like Bim and PUMA.
– FOXO3a downregulates anti-apoptotic proteins like FLIP.
– FOXO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines.
**FOXO3 in Stem Cells**:
– FOXO3 regulates the Notch signaling pathway in adult stem cells.
– FOXO3a protects stem cells from oxidative stress by upregulating antioxidants.
– Foxo3 knockout mice show age-dependent infertility in females.
– FOXO3 is involved in muscle regeneration and self-renewal of stem cells.
– FOXO3 is crucial for maintaining stem cell quiescence.
**FOXO3 in Clinical Significance**:
– Deregulation of FOXO3a is linked to tumorigenesis.
– FOXO3a is downregulated in cancer due to increased Akt activity.
– FOXO3 is known as a tumor suppressor.
– Ketone body β-hydroxybutyrate increases FOXO3a gene expression.
– Plasma levels of β-hydroxybutyrate rise with fasting or a ketogenic diet.
**FOXO3 and Longevity**:
– Genetic variation in FOXO3 is associated with healthspan and longevity in humans.
– FOXO3 is found in most centenarians worldwide.
– Homologous genes in nematodes and fruit flies are linked to longevity.
– Mice lacking FOXO3 do not show accelerated aging or shortened lifespan.
– FOXO3: A Major Gene for Human Longevity–A Mini-Review.
Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.
