Search results for: subunit
#32745724 2020/07/31 To Up
"JANUS" EFFICACY OF CX-5011: CK2 INHIBITION AND METHUOSIS INDUCTION BY INDEPENDENT MECHANISMS.Methuosis has been described as a distinctive form of cell death characterized by the displacement of large fluid-filled vacuoles derived from uncontrolled macropinocytosis. Its induction has been proposed as a new strategy against cancer cells. Small molecules, such as indole-based calchones, have been identified as methuosis inducers and, recently, the CK2 inhibitor CX-4945 has been shown to have a similar effect on different cell types. However, the contribution of protein kinase CK2 to methuosis signalling is still controversial. Here we show that methuosis is not related to CK2 activity since it is not affected by structurally unrelated CK2 inhibitors and genetic reduction/ablation of CK2 subunits. Interestingly, CX-5011, a CK2 inhibitor related to CX-4945, behaves as a CK2-independent methuosis inducer, four times more powerful than its parental compound and capable to promote the formation on enlarged cytosolic vacuoles at low micromolar concentrations. We show that pharmacological inhibition of the small GTPase Rac-1, its downregulation by siRNA treatment, or the over-expression of the dominant-negative mutated form of Rac-1 (Rac-1 T17N), impairs CX-5011 ability to induce methuosis. Furthermore, cell treatment with CX-5011 induces a durable activation of Rac-1 that persists for at least 24 hours. Worthy of note, CX-5011 is able to promote macropinocytosis not only in mammalian cells, but also in an in-vivo zebrafish model. Based on these evidences, CX-5011 is, therefore, proposed as a potential promising compound for cancer therapies for its dual efficacy as an inhibitor of the pro-survival kinase CK2 and inducer of methuosis.
Claudio D'Amore, Enrico Moro, Christian Borgo, Kenichiro Itami, Tsuyoshi Hirota, Lorenzo A Pinna, Mauro Salvi
1309 related Products with: "JANUS" EFFICACY OF CX-5011: CK2 INHIBITION AND METHUOSIS INDUCTION BY INDEPENDENT MECHANISMS.5mg200ug5mg5mg48 samples1 mg50 ug 10mg100mg96 assays 5mg
#32744782 2020/08/03 To Up
Inhibition of the PI 3-kinase pathway disrupts the unfolded protein response and reduces sensitivity to ER stress-dependent apoptosis.Class Ia phosphoinositide 3-kinases (PI3K) are critical mediators of insulin and growth factor action. We have demonstrated that the p85α regulatory subunit of PI3K modulates the unfolded protein response (UPR) by interacting with and regulating the nuclear translocation of XBP-1s, a transcription factor essential for the UPR. We now show that PI3K activity is required for full activation of the UPR. Pharmacological inhibition of PI3K in cells blunts the ER stress-dependent phosphorylation of IRE1α and PERK, decreases induction of ATF4, CHOP, and XBP-1 and upregulates UPR target genes. Cells expressing a human p85α mutant (R649W) previously shown to inhibit PI3K, exhibit decreased activation of IRE1α and PERK and reduced induction of CHOP and ATF4. Pharmacological inhibition of PI3K, overexpression of a mutant of p85α that lacks the ability to interact with the p110α catalytic subunit (∆p85α) or expression of mutant p85α (R649W) in vivo, decreased UPR-dependent induction of ER stress response genes. Acute tunicamycin treatment of R649W mice revealed reduced induction of UPR target genes in adipose tissue, whereas chronic tunicamycin exposure caused sustained increases in UPR target genes in adipose tissue. Finally, R649W cells exhibited a dramatic resistance to ER stress-dependent apoptosis. These data suggest that PI3K pathway dysfunction causes ER stress that may drive the pathogenesis of several diseases including Type 2 diabetes and various cancers.
Jonathon N Winnay, Marie H Solheim, Masaji Sakaguchi, Pål R Njølstad, C Ronald Kahn
2293 related Products with: Inhibition of the PI 3-kinase pathway disrupts the unfolded protein response and reduces sensitivity to ER stress-dependent apoptosis.1mg2 Pieces/Box102 Pieces/Box2100 U2 Pieces/Box2 Pieces/Box
#32744761 2020/08/03 To Up
α integrins in Schwann cells promote attachment to axons, but are dispensable in vivo.In the developing peripheral nervous system, Schwann cells (SCs) extend their processes to contact, sort, and myelinate axons. The mechanisms that contribute to the interaction between SCs and axons are just beginning to be elucidated. Using a SC-neuron coculture system, we demonstrate that Arg-Gly-Asp (RGD) peptides that inhibit α -containing integrins delay the extension of SCs elongating on axons. α integrins in SC localize to sites of contact with axons and are expressed early in development during radial sorting and myelination. Short interfering RNA-mediated knockdown of the α integrin subunit also delays SC extension along axons in vitro, suggesting that α -containing integrins participate in axo-glial interactions. However, mice lacking the α subunit in SCs, alone or in combination with the potentially compensating α subunit, or the α partners β or β , myelinate normally during development and remyelinate normally after nerve crush, indicating that overlapping or compensatory mechanisms may hide the in vivo role of RGD-binding integrins.
Kathleen K Catignas, Luciana R Frick, Marta Pellegatta, Edward Hurley, Zachary Kolb, Kathryn Addabbo, Joseph H McCarty, Richard O Hynes, Arjan van der Flier, Yannick Poitelon, Lawrence Wrabetz, Maria Laura Feltri
2642 related Products with: α integrins in Schwann cells promote attachment to axons, but are dispensable in vivo.96 tests1 mg1.00 flask 1 G5010 ug1x10e7 cells96 wells (1 kit)
#32744742 2020/08/03 To Up
Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.Parvalbumin-positive (PV ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2 PV interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2, we found a potential association of the mutations with mental/neurological abnormalities.
Berta Sanz-Morello, Ulrich Pfisterer, Nikolaj Winther Hansen, Samuel Demharter, Ashish Thakur, Katsunori Fujii, Sergey A Levitskii, Alexia Montalant, Irina Korshunova, Pradeep Pa Mammen, Piotr Kamenski, Satoru Noguchi, Blanca Irene Aldana, Karin Sørig Hougaard, Jean-François Perrier, Konstantin Khodosevich
2349 related Products with: Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.100 ul 100ul100 ul 100ul16100 ul100 ul100ug100μg
#32744500 2020/08/03 To Up
NuRD subunit CHD4 regulates super-enhancer accessibility in Rhabdomyosarcoma and represents a general tumor dependency.The NuRD complex subunit CHD4 is essential for fusion-positive rhabdomyosarcoma (FP-RMS) survival, but the mechanisms underlying this dependency are not understood. Here, a NuRD-specific CRISPR screen demonstrates that FP-RMS is particularly sensitive to CHD4 amongst the NuRD members. Mechanistically, NuRD complex containing CHD4 localizes to super-enhancers where CHD4 generates a chromatin architecture permissive for the binding of the tumor driver and fusion protein PAX3-FOXO1, allowing downstream transcription of its oncogenic program. Moreover, CHD4 depletion removes HDAC2 from the chromatin, leading to an increase and spread of histone acetylation, and prevents the positioning of RNA Polymerase 2 at promoters impeding transcription initiation. Strikingly, analysis of genome-wide cancer dependency databases identifies CHD4 as a general cancer vulnerability. Our findings describe CHD4, a classically defined repressor, as positive regulator of transcription and super-enhancer accessibility as well as establish this remodeler as an unexpected broad tumor susceptibility and promising drug target for cancer therapy.
Joana G Marques, Berkley E Gryder, Blaz Pavlovic, Yeonjoo Chung, Quy A Ngo, Fabian Frommelt, Matthias Gstaiger, Young Song, Katharina Benischke, Dominik Laubscher, Marco Wachtel, Javed Khan, Beat W Schäfer
1318 related Products with: NuRD subunit CHD4 regulates super-enhancer accessibility in Rhabdomyosarcoma and represents a general tumor dependency.
#32744497 2020/08/03 To Up
EDF1 coordinates cellular responses to ribosome collisions.Translation of aberrant mRNAs induces ribosomal collisions, thereby triggering pathways for mRNA and nascent peptide degradation and ribosomal rescue. Here we use sucrose gradient fractionation combined with quantitative proteomics to systematically identify proteins associated with collided ribosomes. This approach identified Endothelial differentiation-related factor 1 (EDF1) as a novel protein recruited to collided ribosomes during translational distress. Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collision interface. EDF1 recruits the translational repressors GIGYF2 and EIF4E2 to collided ribosomes to initiate a negative-feedback loop that prevents new ribosomes from translating defective mRNAs. Further, EDF1 regulates an immediate-early transcriptional response to ribosomal collisions. Our results uncover mechanisms through which EDF1 coordinates multiple responses of the ribosome-mediated quality control pathway and provide novel insights into the intersection of ribosome-mediated quality control with global transcriptional regulation.
Niladri K Sinha, Alban Ordureau, Katharina Best, James A Saba, Boris Zinshteyn, Elayanambi Sundaramoorthy, Amit Fulzele, Danielle M Garshott, Timo Denk, Matthias Thoms, Joao A Paulo, Wade Harper, Eric J Bennett, Roland Beckmann, Rachel Green2 modules30 m Pcs Per Pack 100 G5x96 well plate 100 G25 mg100 ul3x 500 ml1 module200 ug1 mg
#32744327 2020/08/03 To Up
The composition and turnover of the Arabidopsis thaliana 80S cytosolic ribosome.Cytosolic 80S ribosomes contain proteins of the mature cytosolic ribosome (r-proteins) as well as proteins with roles in ribosome biogenesis, protein folding or modification. Here we refined the core r-protein composition in Arabidopsis thaliana by determining the abundance of different proteins during enrichment of ribosomes from cell cultures using peptide mass spectrometry. The turnover rates of 26 40S subunit r-proteins and 29 60S subunit r-proteins were also determined, showing that half of the ribosome population is replaced every 3-4 days. Three enriched proteins showed significantly shorter half-lives; a protein annotated as a ribosomal protein uL10 (RPP0D, At1g25260) with a half-life of 0.5 days and RACK1b and c with half-lives of 1-1.4 days. The At1g25260 protein is a homolog of the human Mrt4 protein, a trans-acting factor in the assembly of the pre-60S particle, while RACK1 has known regulatory roles in cell function beyond its role in the 40S subunit. Our experiments also identified 58 proteins that are not from r-protein families but co-purify with ribosomes and co-express with r-proteins; 26 were enriched more than 10-fold during ribosome enrichment. Some of these enriched proteins have known roles in translation, while others are newly proposed ribosome-associated factors in plants. This analysis provides an improved understanding of Arabidopsis thaliana ribosome protein content, shows that most r-proteins turnover in unison in vivo, identifies a novel set of potential plant translatome components, and how protein turnover can help identify r-proteins involved in ribosome biogenesis or regulation in plants.
Karzan Jalal Salih, Owen Duncan, Lei Li, Josua Trösch, A Harvey Millar
2006 related Products with: The composition and turnover of the Arabidopsis thaliana 80S cytosolic ribosome.min 2 cartons100.00 ul1200 units11 ml1500 Units11mg
#32744323 2020/08/03 To Up
Lnc RNA ZFAS1 regulates the proliferation, apoptosis, inflammatory response and autophagy of fibroblast-like synoviocytes via miR-2682-5p/ADAMTS9 axis in Rheumatoid Arthritis.Rheumatoid arthritis (RA) is a frequent autoimmune disease. Emerging evidence indicated that ZNFX1 antisense RNA1 (ZFAS1) participates in the physiological and pathological processes in RA. However, knowledge of ZFAS1 in RA is limited, the potential work pathway of ZFAS1 needs to be further investigated.
Shanshan Yang, Wei Yin, Yan Ding, Fan Liu
1657 related Products with: Lnc RNA ZFAS1 regulates the proliferation, apoptosis, inflammatory response and autophagy of fibroblast-like synoviocytes via miR-2682-5p/ADAMTS9 axis in Rheumatoid Arthritis.100ul200ul100 ug100 ml.2 Pieces/Box100μg1100ul200ul 100 UG
#32743737 2020/08/02 To Up
A Novel Interaction of Translocator Protein 18 kDa (TSPO) with NADPH Oxidase in Microglia.In the brain neuropil, translocator protein 18 kDa (TSPO) is a stress response protein that is upregulated in microglia and astrocytes in diverse central nervous system pathologies. TSPO is widely used as a biomarker of neuroinflammation in preclinical and clinical neuroimaging studies. However, there is a paucity of knowledge on the function(s) of TSPO in glial cells. In this study, we explored a putative interaction between TSPO and NADPH oxidase 2 (NOX2) in microglia. We found that TSPO associates with gp91 and p22, the principal subunits of NOX2 in primary murine microglia. The association of TSPO with gp91 and p22 was observed using co-immunoprecipitation, confocal immunofluorescence imaging, and proximity ligation assay. We found that besides gp91 and p22, voltage-dependent anion channel (VDAC) also co-immunoprecipitated with TSPO consistent with previous reports. When we compared lipopolysaccharide (LPS) stimulated microglia to vehicle control, we found that a lower amount of gp91 and p22 protein co-immunoprecipitated with TSPO suggesting a disruption of the TSPO-NOX2 subunits association. TSPO immuno-gold electron microscopy confirmed that TSPO is present in the outer mitochondrial membrane but it is also found in the endoplasmic reticulum (ER), mitochondria-associated ER membrane (MAM), and in the plasma membrane. TSPO localization at the MAM may represent a subcellular site where TSPO interacts with gp91 and p22 since the MAM is a point of communication between outer mitochondria membrane proteins (TSPO) and ER proteins (gp91 and p22) where they mature and form the cytochrome b (Cytb) heterodimer. We also found that an acute burst of reactive oxygen species (ROS) increased TSPO levels on the surface of microglia and this effect was abrogated by a ROS scavenger. These results suggest that ROS production may alter the subcellular distribution of TSPO. Collectively, our findings suggest that in microglia, TSPO is associated with the major NOX2 subunits gp91 and p22. We hypothesize that this interaction may regulate Cytb formation and modulate NOX2 levels, ROS production, and redox homeostasis in microglia.
Meredith K Loth, Sara R Guariglia, Diane B Re, Juan Perez, Vanessa Nunes de Paiva, Jennifer L Dziedzic, Jeremy W Chambers, Diana J Azzam, Tomás R Guilarte
2563 related Products with: A Novel Interaction of Translocator Protein 18 kDa (TSPO) with NADPH Oxidase in Microglia.1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set
#32743725 2020/08/03 To Up
Molecular identification of Cryptosporidium spp. in pet snakes in Beijing, China.Few reports of Cryptosporidium spp. in snakes in China have been published. To determine the infection rate and document the presence of Cryptosporidium in pet snakes using molecular methods, 273 fecal samples were collected from eight species of pet snakes from 13 pet households in Beijing, China, and were examined by PCR amplification of the small subunit ribosomal RNA gene. Cryptosporidium was detected from 17 of 273 (6.2%) samples, and nine out of 13 households tested positive for Cryptosporidium with a range of 3.3 to 33.3% among households showing significant difference (p < 0.01). The infection rate of Cryptosporidium for females and males was 6.5% (13/201) and 5.6% (4/72), respectively, showing no significant difference (p > 0.05). Six out of eight pet snake species tested positive for Cryptosporidium with a range of 4.2 to 9.1% among species, showing no significant difference (p > 0.05). Two Cryptosporidium species were identified: Cryptosporidium serpentis in 10 samples and Cryptosporidium varanii in seven samples. No zoonotic Cryptosporidium species occur in our study populations.
Haixia Zhang, Zixiang Lin, Yuxi Jiang, Weifeng Qian, Chaochao Lv, Liwei Zhang, Siqi Wang, Meng Qi, Zhaofei Xia
1884 related Products with: Molecular identification of Cryptosporidium spp. in pet snakes in Beijing, China.1 mL1mg1 mg5010100 μg10 100 μg
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