Brefeldin A and M-COPA block the export of RTKs from the endoplasmic reticulum via simultaneous inactivation of ARF1, ARF4, and ARF5.

Normal receptor tyrosine kinases (RTKs) need to reach the plasma membrane (PM) for ligand-induced activation, whereas its cancer-causing mutants can be activated before reaching the PM in organelles, such as the Golgi/trans-Golgi network (TGN). Inhibitors of protein export from the endoplasmic reticulum (ER), such as brefeldin A (BFA) and 2-methylcoprophilinamide (M-COPA), can suppress the activation of mutant RTKs in cancer cells, suggesting that RTK mutants cannot initiate signaling in the ER. BFA and M-COPA block the function of ADP-ribosylation factors (ARFs) that play a crucial role in ER-Golgi protein trafficking.

Gas-Selective Catalytic Regulation by a Newly Identified Globin-Coupled Sensor Phosphodiesterase Containing an HD-GYP Domain from the Human Pathogen .

Globin-coupled sensors constitute an important family of heme-based gas sensors, an emerging class of heme proteins. In this study, we have identified and characterized a globin-coupled sensor phosphodiesterase containing an HD-GYP domain (GCS-HD-GYP) from the human pathogen , which is an emerging foodborne pathogen of increasing public health concern. The amino acid sequence encoded by the gene from indicated the presence of an N-terminal globin domain and a C-terminal HD-GYP domain, with HD-GYP domains shown previously to display phosphodiesterase activity toward bis(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP), a bacterial second messenger that regulates numerous important physiological functions in bacteria, including in bacterial pathogens.

Apelin expression is downregulated in T cells in a murine model of chronic colitis.

Apelin (APL), an endogenous ligand for APJ, has been reported to be upregulated in a murine model of acute colitis induced by sodium dextran sulfate, as well as inflammatory bowel diseases (IBD) in humans. However, the mechanisms and functions of APL/APJ axis in the pathogenesis of IBD are unclear. We herein analyzed CD4 T cells to determine the functions of APL in a murine model of chronic colitis induced in Rag deficient mice (Rag).

Phosphacan acts as a repulsive cue in murine and rat cerebellar granule cells in a TAG-1/GD3 rafts-dependent manner.

Phosphacan, a chondroitin sulfate proteoglycan, is a repulsive cue of cerebellar granule cells. This study aims to explore the molecular mechanism. The glycosylphosphatidylinositol-anchored neural adhesion molecule TAG-1 is a binding partner of phosphacan, suggesting that the repulsive effect of phosphacan is possibly because of its interaction with TAG-1.

Characterization of a Cobalt-Substituted Globin-Coupled Oxygen Sensor Histidine Kinase from sp. Fw109-5: Insights into Catalytic Regulation by Its Heme Coordination Structure.

Heme-based gas sensors are an emerging class of heme proteins. GcHK, a globin-coupled histidine kinase from sp. Fw109-5, is an oxygen sensor enzyme in which oxygen binding to Fe(II) heme in the globin sensor domain substantially enhances its autophosphorylation activity.

FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells.

FMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are found in 30-40% of acute myelogenous leukemia (AML) patients. Thus, drugs for molecular targeting of FLT3 mutants have been developed for the treatment of AML.

Accelerated Redox Reaction of Hydrogen Peroxide by Employing Locally Concentrated State of Copper Catalysts on Polymer Chain.

Copper complexes act as catalysts for redox reactions to generate reactive oxygen species that destroy biomolecules and, therefore, are utilized to design drugs including antitumor and antibacterial medicines. Especially, catalytic reaction for hydrogen peroxide decomposition is important because it includes the process for generating highly toxic hydroxyl radical, i.e.

Total Synthesis of Violaceoid A and (-)- and (+)-Violaceoid B.

The first total synthesis of violaceoid A, a cytotoxic agent, and the asymmetric total synthesis of (-)- and (+)-violaceoid B are reported. The precursor was accessed by desymmetrization of a substituted quinol moiety, and the racemic secondary alcohol was kinetically resolved using a chiral nucleophilic catalyst. The asymmetric synthesis of (-)- and (+)-violaceoid B elucidated the absolute configuration of the naturally occurring violaceoid B.

Tamoxifen inhibits the proliferation of non‑melanoma skin cancer cells by increasing intracellular calcium concentration.

Tamoxifen is an estrogen receptor (ER) antagonist used as first-line chemotherapy in breast cancer. Recent studies suggest that tamoxifen may be effective not only for ER‑positive but also for ER‑negative cancer cases. The aim of the present study was to investigate the antiproliferative effect of tamoxifen against human non‑melanoma skin cancer cells.

Anti-proliferative effect of ridaifen-B on hepatoma cells.

Ridaifens (RIDs), a novel series of tamoxifen derivatives, exhibit a potent growth-inhibitory effect against numerous tumor cells regardless of the expression of estrogen receptors, and are thus promising candidates as novel anti-tumor drugs. RID-B is a first generation RIDs, and inhibits the proliferation of several tumor cell lines. However, the potentially growth inhibitory effect of RID-B against hepatoma cells, and the detailed mechanism underlying RID-B-mediated tumor cell death remain to be elucidated.

SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation.

Stromal cell-derived factor-1α (SDF-1α)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002.

Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis.

It has been suggested that prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2) expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear.

Clot retraction is mediated by factor XIII-dependent fibrin-αIIbβ3-myosin axis in platelet sphingomyelin-rich membrane rafts.

Membrane rafts are spatially and functionally heterogenous in the cell membrane. We observed that lysenin-positive sphingomyelin (SM)-rich rafts are identified histochemically in the central region of adhered platelets where fibrin and myosin are colocalized on activation by thrombin. The clot retraction of SM-depleted platelets from SM synthase knockout mouse was delayed significantly, suggesting that platelet SM-rich rafts are involved in clot retraction.

Differential genotoxicity of chemical properties and particle size of rare metal and metal oxide nanoparticles.

Nanoparticles of rare metal compounds are used in various products. However, their carcinogenicity and genotoxicity have not been sufficiently evaluated. The tumor-initiating and -promoting potentials of four rare metals, indium oxide (In2O3), dysprosium oxide (Dy2O3), tungsten oxide (WO3) and molybdenum (Mo), with a well-defined particle diameter were evaluated.

VLA-5-mediated adhesion to fibronectin accelerates hemin-stimulated erythroid differentiation of K562 cells through induction of VLA-4 expression.

Fibronectin plays important roles in erythropoiesis through the fibronectin receptors VLA-4 and VLA-5. However, the substantial role of these fibronectin receptors and their functional assignment in erythroid differentiation are not yet fully understood. Here, we investigated the effects of cell adhesion to fibronectin on erythroid differentiation using K562 human erythroid progenitor cells.

Proliferative effects of bovine and porcine thyroglobulins on thyroid epithelial cells.

Thyroglobulin is the precursor of the thyroid hormones, triiodothyronine and thyroxine. Because the molecular size of thyroglobulin is relatively large (660 kDa), it could have other additional functions besides serving as the precursor of the thyroid hormones. In this report, we examined the proliferative effects of thyroglobulins purified from bovine and porcine thyroid tissues on the growth of a rat thyroid follicular cell line, FRTL-5, as well as the primary culture of porcine thyroid epithelial cells.

Impact of plasminogen on an in vitro wound healing model based on a perfusion cell culture system.

Vascular reorganization in wound healing is a complex process, which involves coagulation, endothelial cell proliferation and migration, basement membrane regeneration, and fibrinolysis. During this healing process, the hemostatic system and the angiogenic system are intimately interconnected. To elucidate the contribution of plasminogen in the process of wound healing, we have established a perfusion cell culture system.

Plasminogen N-terminal activation peptide modulates the activity of angiostatin-related peptides on endothelial cell proliferation and migration.

Angiostatin, a potent inhibitor of angiogenesis, is derived from the fibrinolytic proenzyme, plasminogen, by enzymatic processing. Plasminogen N-terminal activation peptide (PAP) is one of the products concomitantly released aside from angiostatin (kringles 1-4) and mini-plasminogen (kringle 5 plus the catalytic domain) when plasminogen is processed. To determine whether PAP alone or together with the angiostatin-related peptides derived from the processing of plasminogen modulate the proliferation and motility of endothelial cells, we have generated a recombinant PAP and used it to study its effects on endothelial cells in the presence and absence of the angiostatin-related peptides.

Reduced sulfation of chondroitin sulfate in thyroglobulin derived from human papillary thyroid carcinomas.

The presence of a chondroitin sulfate (CS) chain on human thyroglobulin (Tg) distinguishes it from Tg of other species; the role played by this chain in normal thyroid function is unclear. In the present study, we determined the structure of the CS oligosaccharides in human thyroid-derived Tg. Q-Sepharose anion exchange column chromatography of thyroid extracts indicated that the negative charge of human Tg was primarily due to the presence of the CS chain.