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Results for “Forkhead Box Protein O3”

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PubMed2025

Multiplexed Dual-Color Fluorescence-Based Distinction Between Nuclear Trapping and Translocation of FOXO3.

FOXO3 is a transcription factor that mainly exerts its functions in the cell nucleus. The amino acid sequence of FOXO3 contains a nuclear localization sequence (NLS) and a nuclear export sequence (NES) allowing for nuclear/cytoplasmic shuttling that plays an important role in regulating FOXO3 activity. Nuclear accumulation of FOXO3 proteins can be the result of translocation to the nucleus triggered by upstream regulatory input or trapping of FOXO3 within the nucleus through the inhibition of its nuclear export via the receptor CRM1. In order to distinguish these two modes of FOXO3 activation, we have generated a multiplexed assay. The development of this platform includes a reporter cell line that monitors CRM1 activity by using RFP-labeled HIV-1 Rev. protein with a strong heterologous NES. Simultaneously, the intracellular localization of FOXO3 can be monitored by a second cell line stably expressing GFP-FOXO3. Here we describe a detailed protocol on how to co-culture these reporter cell lines and use them to interrogate compound-induced FOXO3 activation in order to understand the mode of action.

Forkhead Box Protein O3↗

PubMed2026

Participation of the purinergic P2X7 receptor in molecular complexes in the nucleus of human chondrocytes.

In addition to the purinergic receptor P2X7R's known activity as a sensor of damage-associated molecular patterns (DAMPs), evidences support its role in maintaining tissue homeostasis. Its presence in cellular compartments other than its usual transmembrane localization suggests its involvement in specific signaling pathways. This study aimed to analyze P2X7R in the nucleus of human chondrocytes and search for potential interacting partners. Through co-immunoprecipitation and proximity ligation assay we discovered that, independent of extracellular ATP levels, P2X7R is abundantly present in both the nuclear membrane and in the nucleoplasm, where it is found in close proximity to lamin A/C (a component of the nuclear lamina), emerin (a protein involved in the assembly and disassembly of the nuclear envelope), and SUN2 (an inner nuclear membrane protein that facilitates the transmission of mechanical forces). Furthermore, chromatin immunoprecipitation revealed the participation of P2X7R in molecular complexes located in the promoter of specific genes including Sox9, TRPS1, FOXO3a, integrin β2 and connective tissue growth factor. Overall, this evidence reveals for the first time novel partners of P2X7R that place it in an intricate network that influences nuclear structure, mechanosensitivity, chromatin organization, and gene expression. Specifically, on the one hand, a close association between P2X7R and nuclear proteins participating in the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex (lamin A/C, emerin, and SUN2) places it among the factors involved in mechanosignaling and the maintenance of nuclear integrity; on the other, its recruitment to specific gene promoters suggests that it may act as a transcription regulator.

Humans↗

PubMed2026

UNCX/SIN3A-Mediated H4K8 decrotonylation suppresses FOXO3 to drive TNBC progression and docetaxel resistance.

Triple-negative breast cancer (TNBC) remains a clinically challenging subtype characterized by aggressive behavior and limited treatment options. Though docetaxel remains a cornerstone chemotherapy for TNBC, the frequent emergence of resistance highlights the urgent need to identify novel therapeutic targets. In this study, we report that uncoordinated homeobox (UNCX) is upregulated in docetaxel-resistant breast cancer cells, genomically amplified in breast cancer, and associated with poor survival in breast carcinoma patients. Functional studies revealed that UNCX promotes breast cancer cell proliferation, migration and reduces the docetaxel sensitivity. Mechanistically, UNCX functions as a transcriptional repressor by recruiting the SIN3A complex. Genome-wide profiling indicated that the UNCX/SIN3A complex directly binds to the promoters of tumor-suppressor genes including FOXO3, and represses their transcription by removing histone H4K8 crotonylation (H4K8cr). Additionally, the UNCX/SIN3A complex enhances FOXO3 phosphorylation and inhibits its nuclear translocation, further inhibiting its activity. Notably, SIN3A knockdown, FOXO3 overexpression, or crotonylation restoration effectively reverses UNCX-induced malignant phenotypes. These findings collectively establish the UNCX/SIN3A-H4K8cr-FOXO3 axis as a pivotal epigenetic regulator of TNBC progression and chemoresistance, revealing new avenues for targeted therapeutic development against this aggressive breast cancer subtype.

Humans↗

PubMed2025

Mechanism of Qigu capsule as a treatment for sarcopenia based on network pharmacology and experimental validation.

OBJECTIVE: To explore the potential molecular mechanism of Qigu capsule (，QGC) in the treatment of sarcopenia through network pharmacology and to verify it experimentally. METHODS: The active compounds of QGC and common targets between QGC and sarcopenia were screened from databases. Then the herbs-compounds-targets network, and protein-protein interaction (PPI) network was constructed. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed by R software. Next, we used a dexamethasone-induced sarcopenia mouse model to evaluate the anti-sarcopenic mechanism of QGC. RESULTS: A total of 57 common targets of QGC and sarcopenia were obtained. Based on the enrichment analysis of GO and KEGG, we took the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway as a key target to explore the mechanism of QGC on sarcopenia. Animal experiments showed that QGC could increase muscle strength and inhibit muscle fiber atrophy. In the model group, the expression of muscle ring finger-1 and Atrogin-1 were increased, while myosin heavy chain was decreased, QGC treatment reversed these changes. Moreover, compared with the model group, the expressions of p-PI3K, p-Akt, p-mammalian target of rapamycin and p-Forkhead box O3 in the QGC group were all upregulated. CONCLUSION: QGC exerts an anti-sarcopenic effect by activating PI3K/Akt signaling pathway to regulate skeletal muscle protein metabolism.

Sarcopenia↗

PubMed2025

The pathway of autophagy in the epigenetic landscape of Mycobacterium-host interactions.

Macroautophagy (autophagy) is an evolutionarily conserved process that degrades excess cytoplasmic components, such as protein aggregates and damaged organelles, by encapsulating them within double-membrane autophagosomes. These autophagosomes undergo distinct stages - initiation, phagophore nucleation, expansion, and closure - before fusing with lysosomes (or occasionally endosomes) for degradation and recycling. This process is regulated by ATG (autophagy related) proteins, which govern autophagosome formation and lysosomal fusion. Epigenetic modifications and transcription factors can regulate ATG gene expression in the nucleus. Autophagy also plays a key role in eliminating intracellular Mycobacterium tuberculosis (Mtb) through the lytic and antimicrobial activities of autolysosomes, which are more potent antimicrobial compartments than conventional phagosomes. Emerging evidence suggests that Mtb can modify the host epigenome and transcriptional machinery, significantly affecting the host immune response. This review explores the epigenetic regulation of autophagy during mycobacterium-host interactions. The interplay between epigenetic regulation and autophagy highlights a crucial aspect of host-pathogen interactions during Mtb infection. Understanding how Mtb manipulates the host epigenome to regulate autophagy could lead to the development of novel therapeutic strategies that enhance autophagic pathways or counteract Mtb's immune evasion tactics.Abbreviations: AM: Alveolar macrophages; ATG: autophagy related; DNMT: DNA methyltransferase; FOXO3: forkhead box O3; HAT: histone acetyltransferase; HDAC: histone deacetylase; MIR: microRNA; MTOR: mechanistic target of rapamycin kinase; Mtb: Mycobacterium tuberculosis; ROS: reactive oxygen species; SIRT: sirtuin; STPK: serine/threonine protein kinase.

Autophagy↗