Search results for: ASK1(Phospho Ser966)
#32996079 2020/09/29 To Up
Activation of ATM kinase by ROS generated during ionophore-induced mitophagy in human T and B cell malignancies.Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor, also possesses non-nuclear functions owing to its presence in extra-nuclear compartments, including peroxisomes, lysosomes, and mitochondria. ATM is frequently altered in several human cancers. Recently, we and others have shown that loss of ATM is associated with defective mitochondrial autophagy (mitophagy) in ataxia-telangiectasia (A-T) fibroblasts and B-cell lymphomas. Further, we reported that ATM protein but not ATM kinase activity is required for mitophagy. However, the mechanism of ATM kinase activation during ionophore-induced mitophagy is unknown. In the work reported here, using several ionophores in A-T and multiple T-cell and B-cell lymphoma cell lines, we show that ionophore-induced mitophagy triggers oxidative stress-induced ATM phosphorylation through ROS activation, which is different from neocarzinostatin-induced activation of ATM, Smc1, and Kap1. We used A-T cells overexpressed with WT or S1981A (auto-phosphorylation dead) ATM plasmids and show that ATM is activated by ROS-induced oxidative stress emanating from ionophore-induced mitochondrial damage and mitophagy. The antioxidants N-acetylcysteine and glutathione significantly inhibited ROS production and ATM phosphorylation but failed to inhibit mitophagy as determined by retroviral infection with mt-mKeima construct followed by lysosomal dual-excitation ratiometric pH measurements. Our data suggest that while ATM kinase does not participate in mitophagy, it is activated via elevated ROS.
Aloke Sarkar, Varsha Gandhi
1491 related Products with: Activation of ATM kinase by ROS generated during ionophore-induced mitophagy in human T and B cell malignancies.1100 μg96 tests100 μgOne 96-Well Microplate Ki 100ul96 testsOne 96-Well Microplate Ki96T100 μg
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#27364558 2016/06/30 To Up
Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth.Syndecan-1 (Sdc1/CD138) expression is linked to disease severity in multiple myeloma, although the causal basis for this link remains unclear. Here we report that capture of the IGF1 receptor (IGF1R) by Sdc1 suppresses ASK1-dependent apoptosis in multiple myeloma cells. Sdc1 binds two different fractions of IGF1R, one that is constitutively active and a second that is activated by IGF1 ligand. Notably, IGF1R kinase activity in both fractions is blocked by synstatinIGF1R (SSTNIGF1R), a peptide that inhibits IGF1R capture by Sdc1, as well as by a truncated peptide (SSTNIGF1R-T) that appears to be specific for multiple myeloma cells. Mechanistically, we show that ASK1 is bound to active IGF1R and inhibited by Tyr and Ser83/Ser966 phosphorylation. When IGF1R engagement with Sdc1 is blocked by SSTNIGF1R, ASK1 becomes activated, and initiates JNK- and caspase-3-mediated apoptosis. In pharmacologic tests, we find SSTNIGF1R is highly stable in human plasma and displays a half-life of 27 hours in mice, wherein it significantly reduces both the size and neovascularization of CAG myeloma tumor xenografts. Taken together, our results offer a preclinical proof of concept and mechanistic rationale for the exploration of SSTNIGF1R as an experimental therapeutic to dually attack multiple myeloma tumor cell survival and tumor angiogenesis. Cancer Res; 76(17); 4981-93. ©2016 AACR.
DeannaLee M Beauvais, Oisun Jung, Yang Yang, Ralph D Sanderson, Alan C Rapraeger
1224 related Products with: Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth.100ug Lyophilized100ug Lyophilized100ug 100ul100ug100ug100ug100ug100ug Lyophilized
#26095851 2015/06/19 To Up
Cyclophilin A regulates JNK/p38-MAPK signaling through its physical interaction with ASK1.Cyclophilin A (CypA), a member of the immunophilin family, is predominantly localized in the cytoplasm. The peptidylprolyl isomerase (PPIase) activity of CypA has been demonstrated to be involved in diverse cellular processes, including intracellular protein trafficking, mitochondrial function, pre-mRNA processing, and maintenance of multiprotein complex stability. In this study, we have demonstrated that CypA regulates apoptosis signaling-regulating kinase 1 (ASK1) through its direct binding. ASK1 is a member of MAPK kinase kinase (MAP3K) family, and selectively activates both JNK and p38 MAPK pathways. Here, we also report that CypA negatively regulates phosphorylation of ASK1 at Ser966, and that CypA reduces ASK1 and its downstream kinases of the JNK and p38 signaling. ASK1 is known to induce caspase-3 activation and apoptosis, and CypA inhibited ASK1-mediated apoptosis by decrease in caspase-3 activity under cellular stress conditions. Overall, we conclude that CypA negatively regulates ASK1 functions by its physical interaction with ASK1.
Hunsung Kim, Yoojung Oh, Kiyoon Kim, Suyun Jeong, Suk Chon, Daehong Kim, Min Hyung Jung, Youngmi Kim Pak, Joohun Ha, Insug Kang, Wonchae Choe
1240 related Products with: Cyclophilin A regulates JNK/p38-MAPK signaling through its physical interaction with ASK1.1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set
#22977523 2011/03/21 To Up
Functional interaction of BRCA1/ATM-associated BAAT1 with the DNA-PK catalytic subunit.Ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) play a crucial role in the initial stages of cell response, when cells are exposed to DNA insult such as ionizing radiation (IR) and chemical agents. We previously demonstrated that ATM requires BAAT1 for its activation in response to IR. In the present study, BAAT1 was found to bind to the DNA-PK catalytic subunit (DNA-PKcs) and SMC1. Biochemical analysis indicated that several regions of BAAT1 were responsible for the interaction with these proteins, and their binding affinity was altered after treatment with the IR mimetic, neocarzinostatin (NCS). Phosphorylation of the DNA-PKcs at Ser2056 and SMC1 at Ser966 was induced by NCS, while phosphorylation was reduced when BAAT1 was depleted by siRNA. These results indicate that BAAT1 globally regulates DNA damage signaling during the early stages of apoptosis.
Eui Young So, Toru Ouchi
2065 related Products with: Functional interaction of BRCA1/ATM-associated BAAT1 with the DNA-PK catalytic subunit.1 Set1 Set100μg1 Set1 Set1 Set100.00 ul1 Set1 Set1 Set1 Set2
#21390062 2011/03/10 To Up
Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis.DNA damage signaling pathways are initiated in response to chemical reagents and radiation damage, as well as in response to hypoxia. It is implicated that structural maintenance of chromosomes 1 (SMC1) is not only a component of the cohesion complex but also facilitates the activation of DNA damage checkpoint proteins. Here, we studied the mechanism of DNA damage checkpoint activated by ATR-SMC1 pathway when cells are treated with desferrioxamine (DFO), a hypoxia-mimetic reagent. We show that DFO treatment induces phosphorylation of SMC1 at Ser966, NBS1 at Ser343, Chk1 at Ser317, Chk2 at Thr68, and p53 at Ser15. Among these sites, phosphorylation of SMC1, NBS1, and Chk1 by DFO are mediated by ATR as it is greatly reduced in both ATR-deficient human fibroblasts and HCT116 human colon cancer cells in which ATR is heterozygously mutated, whereas these proteins are phosphorylated in cells deficient for ATM and DNA-PKcs. DFO-induced apoptosis is decreased in ATR-mutant HCT116 cells, although p53 is normally activated in those cells. Expression of SMC1 S966A in which Ser966 is substituted to Ala attenuates apoptosis and phosphorylation of Chk1 at Ser317 after DFO treatment, although levels of HIF1α are not significantly changed. These results suggest that DFO induces apoptosis through the ATR-SMC1 arm of the pathway.
E Y So, M Ausman, T Saeki, T Ouchi
1707 related Products with: Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis.50 ul100ug Lyophilized2 Pieces/Box1 LITRE1 mg100ug Lyophilized100 TESTS100ug Lyophilized100ug Lyophilized2 Pieces/Box0.1ml (1mg/ml)100 ml
#17216363 // To Up
Modeling the tertiary structure of the patatin domain of neuropathy target esterase.Neuropathy target esterase (NTE) is a transmembrane protein of unknown function whose specific chemical modification by certain organophosphorus (OP) compounds leads to distal axonopathy. Therefore, solving the 3D structure of NTE would advance the understanding of its pathogenic and physiologic roles. In this study, the tertiary structures of the patatin (catalytic) domain and the N-terminal transmembrane domain of NTE were modeled using the crystal structures of patatin (PDB ID 1oxw) and moricin (PDB ID 1kv4) as templates. Sequence alignments and secondary structure predictions were obtained from the INUB server (Buffalo, NY). O and PyMol were used to build the PNTE and NTE TMD chains from these sequence alignments. The PNTE model was refined in the presence of water using the crystallography and NMR system, while the NTE TMD model was refined in vacuo using the GROMOS implementation in the Swiss PDB viewer. The modeled active site of NTE was found to consist of a Ser966-Asp1086 catalytic dyad, which is characteristic of phospholipase A2 enzymes. The Ser966 Ogamma was located 2.93 A from the Odelta2 of Asp1086. In addition, our NTE model was found to contain a single N-terminal transmembrane domain. This modeling effort provided structural and mechanistic predictions about the catalytic domain of NTE that are being verified via experimental techniques.
Sanjeeva J Wijeyesakere, Rudy J Richardson, Jeanne A Stuckey
1770 related Products with: Modeling the tertiary structure of the patatin domain of neuropathy target esterase.500IUmin 2 cartons 5 G100.00 ul 100 G200 units10.1ml (1mg/ml)1
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