Phosphorylation

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling...

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value...

Plant growth occurs via the interconnection of cell growth and proliferation in each organ following specific developmental and environmental cues. Therefore, different photoperiods result in distinct growth patterns due to the integration of light and circadian perception with specific Carbon (C) partitioning strategies. In addition, the TARGET OF RAPAMYCIN (TOR) kinase pathway is an ancestral signaling pathway that integrates nutrient information with translational control and growth regulation. Recent findings in Arabidopsis (Arabidopsis thaliana) have shown a mutual connection between the TOR pathway and the circadian clock...

Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription...

The present study was aimed to explore the effect of triazole on growth and viability of liver cancer cells. Cell growth was examined using the MTT test and expression of several proteins was assessed by western blotting assay. The Matrigel-coated Transwell assay was employed to examine the infiltration of cells. The data from MTT assay showed that MHCC97H and H4TG liver cancer cell viability was inhibited by triazole in a concentration-dependent manner. After treatment with 0.5, 1.0, 2.0, 4, 8, and 16 µM doses of triazole, the rate of H4TG cell viability was decreased to 96, 73, 58, 39, 29, and 28%, respectively...

BACKGROUND AND OBJECTIVES: Despite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K-AKT-TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models...

UNLABELLED: While the unfolded protein response (UPR) contributes to survival by removing misfolded proteins, ER stress also activates pro-apoptotic pathways. Changed sensitivity to normal developmental stimuli may underlie observed cardiomyocyte apoptosis in the healthy perinatal heart. METHODS: We determined in vitro sensitivity to thapsigargin in sheep cardiomyocytes from four perinatal ages. In utero cardiac activation of endoplasmic reticulum (ER) stress and apoptotic pathways was determined at these same ages...

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins...

Post-translational modifications (PTMs), such as phosphorylation and O-N-acetyl-β-d-glucosaminylation (O-GlcNAcylation), are involved in the fine spatiotemporal regulation of protein functions, and their dynamic interplay is at the heart of protein language. The coexistence of phosphorylation and O-GlcNAcylation on a protein leads to the diversification of proteoforms. It is therefore essential to decipher the phosphorylation/O-GlcNAcylation interplay on protein species that orchestrates cellular processes in a specific physiological or pathophysiological context...

Myosin phosphatase targeting subunit1 (MYPT1) is a critical subunit of myosin phosphatase (MP), which brings PP1Cδ phosphatase and its substrate together. We previously showed that MYPT1 depletion resulted in oblique chromatid segregation. Therefore, we hypothesized that MYPT1 may control microtubule-dependent motor activity. Dynein, a minus-end microtubule motor, is known to be involved in mitotic spindle assembly. We thus examined whether MYPT1 and dynein may interact. Proximity ligation assay and co-immunoprecipitation revealed that MYPT1 and dynein intermediate chain (DIC) were associated...

BACKGROUND: AMP-activated protein kinase (AMPK) is a key enzyme for cellular energy homeostasis and improves metabolic disorders. Brown and beige adipose tissues exert thermogenesis capacities to dissipate energy in the form of heat. Here, we investigated the beneficial effects of the antioxidant alpha-lipoic acid (ALA) in menopausal obesity and the underlying mechanisms. METHODS: Female Wistar rats (8 weeks old) were subjected to bilateral ovariectomy (Ovx) and divided into four groups: Sham (n=8), Ovx (n=11), Ovx+ALA2 (n=10), and Ovx+ALA3 (n=6) (ALA 200 and 300 mg/kg/day, respectively; gavage) for 8 weeks...

Acute myeloid leukaemia (AML) is characterized by uncontrolled proliferation of myeloid progenitor cells and impaired maturation, leading to immature cell accumulation in the bone marrow and bloodstream, resulting in hematopoietic dysfunction. Chemoresistance, hyperactivity of survival pathways, and miRNA alteration are major factors contributing to treatment failure and poor outcomes in AML patients. This study aimed to investigate the impact of the pharmacological p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 on the chemoresistance potential of AML stem cell line KG1a to the therapeutic drug daunorubicin (DNR)...

DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in progression of several cancers 1-4. One of these is small cell lung cancer (SCLC). Our laboratory has demonstrated that the RNA helicase DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration 5. SCLC is an extremely lethal, recalcitrant tumor 6,7, causing 250,000 deaths annually worldwide 8 and currently lacking effective treatments 9,10. Supinoxin (RX 5902), a compound having anti-cancer activity 11, is a known target of phosphor-DDX5 12,13; Supinoxin blocks the interaction between β-catenin and phosphor-DDX5 13, thereby releasing β-catenin and allowing its degradation...

Introduction: It may take decades to develop cardiovascular dysfunction following exposure to high doses of ionizing radiation from medical therapy or from nuclear accidents. Since astronauts may be exposed continually to a complex space radiation environment unlike that experienced on Earth, it is unresolved whether there is a risk to cardiovascular health during long-term space exploration missions. Previously, we have described that mice exposed to a single dose of simplified Galactic Cosmic Ray (GCR5-ion ) develop cardiovascular dysfunction by 12 months post-radiation...

Mesenchymal stem cells (MSCs) possess a strong therapeutic potential in regenerative medicine. ELABELA (ELA) is a 32 amino acid peptide that binds to the apelin peptide jejunum receptor (APJ) to regulate cell proliferation and migration. The aim of this study was to investigate the function of ELA vis-a-vis the MSC proliferation and migration, and further explore the underlying mechanism. We demonstrated that the exogenous supplement of ELA boosts the proliferation and migration ability of MSCs, alongside improved in vitro cell viability...

BACKGROUND: Genetic syndromes of hyperkinetic movement disorders associated with epileptic encephalopathy and intellectual disability are becoming increasingly recognized. Recently, a de novo heterozygous NACC1 (nucleus accumbens-associated 1) missense variant was described in a patient cohort including one patient with a combined mitochondrial oxidative phosphorylation (OXPHOS) deficiency. OBJECTIVES: The objective is to characterize the movement disorder in affected patients with the recurrent c...

BACKGROUND: Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown...

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) is a microbial risk factor whose presence increases the risk of oral squamous cell carcinoma (OSCC) progression. However, whether it can promote the proliferation of OSCC cells remains unknown. METHODS: In this study, we investigated F. nucleatum effect on OSCC cell proliferation using in vitro and in vivo experiments. RESULTS: Our results showed that F. nucleatum promoted OSCC cell proliferation, doubling the cell count after 72 h (CCK-8 assay)...

BACKGROUND: Uveal melanoma (UVM) is a malignant intraocular tumor in adults. Targeting genes related to oxidative phosphorylation (OXPHOS) may play a role in anti-tumor therapy. However, the clinical significance of oxidative phosphorylation in UVM is unclear. METHOD: The 134 OXPHOS-related genes were obtained from the KEGG pathway, the TCGA UVM dataset contained 80 samples, served as the training set, while GSE22138 and GSE39717 was used as the validation set. LASSO regression was carried out to identify OXPHOS-related prognostic genes...

c-Myc is a proto-oncoprotein that regulates various cellular processes and whose abnormal expression leads to tumorigenesis. c-Myc protein stability has been shown to be predominantly controlled by the ubiquitin ligase (E3) CRL1Fbxw7 in a manner dependent on glycogen synthase kinase 3 (GSK3)-mediated phosphorylation. Here we show that, in some types of cancer cells, c-Myc degradation is largely insensitive to the GSK3 inhibitor (GSK3i) CHIR99021, suggesting the existence of an E3 other than CRL1Fbxw7 for c-Myc degradation...