Drug Target and Biomarker: FOXO3 (G2309)

Target Name: FOXO3

NCBI ID: G2309

Drug Target and Biomarker: FOXO3

FOXO3 plays a crucial role in gene expression during terminal erythroid maturation.
LZ-101 stabilizes FOXO3a and induces mitochondrial apoptosis, showing strong anti-tumor activity.
AKT is essential for phosphorylation, nuclear exclusion, and degradation of FOXO3a by TGFbeta, which influences stemness in SCC15 cells.
The AMPK-SKP2-CARM1 signaling axis involving FOXO3a regulates autophagy.
FOXO3a-mediated regulation of ABCB1 influences drug efflux and cross-resistance in cancer cells.

These viewpoints highlight the various roles and mechanisms associated with FOXO3, including its involvement in gene expression, apoptosis induction, stemness regulation, autophagy, and drug resistance.
FOXO3a is a transcription factor that plays a role in various cellular processes, including autophagy, histone modification, apoptosis, and cell growth arrest. Its activation is influenced by different signaling pathways and protein interactions, which ultimately lead to changes in gene expression and cellular outcomes.

In response to glucose starvation, the activation of FOXO3a-dependent autophagy and lysosomal genes is mediated by the CARM1-Pontin-FOXO3a signaling axis, which involves methylated Pontin binding to FOXO3a. Another signaling axis involving TFEB and CARM1 works for CLEAR motifs, activating genes regardless of Pontin methylation status.

CircMRPS35, a circular RNA molecule, has been found to affect the proliferation and metastasis of gastric cancer. It recruits KAT7 to the promoter regions of FOXO1 and FOXO3a, leading to increased H4K5 acetylation and upregulation of these genes.

In osteosarcoma cells, the downregulation of HIPK2 results in the accumulation of CtBP1, which assembles with p300 and FOXO3a to repress the expression of proapoptotic genes, inhibiting apoptosis and increasing chemoresistance. On the other hand, HIPK2 overexpression promotes CtBP1 degradation, preventing the formation of the complex and increasing proapoptotic gene expression, ultimately promoting apoptosis and decreasing chemoresistance.

BMCC1 has been studied for its role in the DNA damage response. Knockdown of BMCC1 decreases phosphorylation signals related to the response to DNA-damaging agents and increases phosphorylation at AKT-T308 and FOXO3a-T32. BMCC1 is proposed to inhibit antiapoptotic proteins in DNA-damaged cells to facilitate mitochondrial apoptosis.

Diosmetin, a natural compound, has been shown to inhibit cell growth in prostate cancer cells. It downregulates c-Myc, cyclin D1, and Cdk4, while increasing FOXO3a and p27Kip1 expression levels, leading to cell growth arrest. Diosmetin treatment also enhances the apoptotic machinery in prostate cancer cells.

Overall, FOXO3a is involved in multiple cellular processes and its activity is regulated by various signaling pathways and protein interactions. These findings highlight the importance of FOXO3a in cellular homeostasis and shed light on potential therapeutic targets for various diseases.

Protein Name: Forkhead Box O3

Functions: Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy (PubMed:10102273, PubMed:16751106, PubMed:21329882, PubMed:30513302). Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins (By similarity). Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (PubMed:10102273, PubMed:16751106). Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription (PubMed:23283301). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity). Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3 (PubMed:30513302)

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