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81.
Shano S Hatanaka K Ninose S Moriyama R Tsujiuchi T Fukushima N 《Biochimica et biophysica acta》2008,1783(5):748-759
Lysophosphatidic acid (LPA) is an extracellular signaling lipid that regulates cell proliferation, survival, and motility of normal and cancer cells. These effects are produced through G protein-coupled LPA receptors, LPA(1) to LPA(5). We generated an LPA(1) mutant lacking the SerValVal sequence of the C-terminal PDZ-binding domain to examine the role of this domain in intracellular signaling and other cellular functions. B103 neuroblastoma cells expressing the mutant LPA(1) showed rapid cell proliferation and tended to form colonies under serum-free conditions. The enhanced cell proliferation of the mutant cells was inhibited by exogenous expression of the plasmids inhibiting G proteins including G(betagamma), G(alphai) and G(alphaq) or G(alpha12/13), or treatment with pertussis toxin, phosphoinositide 3-kinase (PI3K) inhibitors or a Rho inhibitor. We confirmed that the PI3K-Akt and Rho pathways were intrinsically activated in mutant cells by detecting increases in phosphorylated Akt in western blot analyses or by directly measuring Rho activity. Interestingly, expression of the mutant LPA(1) in non-tumor mouse fibroblasts induced colony formation in a clonogenic soft agar assay, indicating that oncogenic pathways were activated. Taken together, these observations suggest that the mutant LPA(1) constitutively activates the G protein signaling leading to PI3K-Akt and Rho pathways, resulting in enhanced cell proliferation. 相似文献
82.
Mutated SEA-D227A-conjugated antibodies greatly enhance antitumor activity against MUC1-expressing bile duct carcinoma 总被引:8,自引:0,他引:8
Hideaki Kodama Masanori Suzuki Yu Katayose Masao Shinoda Naoki Sakurai Shin-ichi Takemura Hiroshi Yoshida Hisaaki Saeki Masahiko Ichiyama Kohei Tsumoto Ryutaro Asano Izumi Kumagai Kohzoh Imai Yuji Hinoda Seiki Matsuno Toshio Kudo 《Cancer immunology, immunotherapy : CII》2001,50(10):539-548
For the purpose of establishing a new adoptive immunotherapy for bile duct carcinoma (BDC), we have directed our attention to superantigens (SAgs), the most potent known activators of T lymphocytes. In our previous study, staphylococcal enterotoxin A (SEA) was conjugated chemically with MUSE11 mAb, which recognizes the MUC1 cancer-associated antigen, and shown to enhance the specific cytotoxic activity of T-LAK cells against MUC1-expressing BDC cells (TFK-1) in vitro and in vivo. However, it is probable that SEA might cause side-effects because of nonspecific binding to class II positive cells. In order to overcome these, we generated mutated SEA (mSEA) by changing Asp at position 227 of native SEA to Ala, which has reduced affinity to MHC class II molecules, but retains the potential for T cell activation. When mSEA-D227A was administered to rabbits to examine effects on blood pressure, 500 times more mSEA-D227A was tolerated than native SEA. This prompted us to construct a mSEA-D227A-conjugated mAb, reactive with MUC1. It augmented the antitumor activity of T-LAK cells significantly, and furthermore, mSEA-D227A could be conjugated to two bispecific antibodies, BsAb (anti-MUC1 x anti-CD3) and BsAb (anti-MUC1 x anti-CD28), which in combination had greater enhancing effects than mSEA-D227A-conjugated anti-MUC1 mAb, and combination of unconjugated BsAbs. These findings indicate a utility of mSEA-D227A-conjugated antibodies for targeted cancer immunotherapy. 相似文献
83.
J Sun N Takahashi H Kakinuma Y Nishi 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(10):5775-5785
Catalytic Abs (catAbs) preferentially evolved in autoimmune MRL/MPJ-lpr/lpr (MRL/lpr) mice upon immunization with the phosphonate transition-state analogue (TSA), but this did not happen in normal BALB/c mice. The majority of the catAbs from MRL/lpr mice were from several independent clones of the same family. Most of them had a lysine at position 95 in the heavy chain (H95), which is at the junctional region. This residue, which interacts with the phosphonate moiety of the TSA and presumably is involved in the catalytic activity, was not changed even after expansive evolution following multiple mutations. By contrast, the majority that arose from BALB/c mice were the non-catAbs, which were quite different in the sequence from the catAbs from MRL/lpr mice, but they were clonally related to one another, so most of them were originated from a single clone. In the MRL/lpr mice, the catalytic subsets that existed in the initial repertoire were effectively captured by the phosphonyl oxygens in the TSA by interacting with the lysine at H95. In the BALB/c mice, however, another noncatalytic subset with only the binding capability directed to a moiety other than the phosphonate moiety was alternatively evolved, because of the lowest abundance or elimination of the catalytic subsets. 相似文献
84.
Katsumi Kakinuma Noboru Ōtake Hiroshi Yonehara 《Bioscience, biotechnology, and biochemistry》2013,77(12):2529-2538
The structure of detoxin D1, one of the main active principles of detoxio complex, has been established on the basis of the degradative studies and spectral evidences as depicted in formula (I).Detoxin D1 has been demonstrated to belong to a new class of the depsipeptide contained an amino acid designated detoxinine which was newly isolated as a natural product. 相似文献
85.
86.
Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis 下载免费PDF全文
Pietro Fratta Jose M Brito‐Armas Bernadett Kalmar Agnieszka Ule Yichao Yu Nicol Birsa Cristian Bodo Toby Collins Alexander E Conicella Alan Mejia Maza Alessandro Marrero‐Gagliardi Michelle Stewart Joffrey Mianne Silvia Corrochano Warren Emmett Gemma Codner Michael Groves Ryutaro Fukumura Yoichi Gondo Mark Lythgoe Erwin Pauws Emma Peskett Philip Stanier Lydia Teboul Martina Hallegger Andrea Calvo Adriano Chiò Adrian M Isaacs Nicolas L Fawzi Eric Wang David E Housman Francisco Baralle Linda Greensmith Emanuele Buratti Vincent Plagnol Abraham Acevedo‐Arozena 《The EMBO journal》2018,37(11)
TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages. 相似文献
87.
Tomoyuki Ohe Ryutaro Umezawa Yumina Kitagawara Daisuke Yasuda Kyoko Takahashi Shigeo Nakamura Akiko Abe Shuichi Sekine Kousei Ito Kentaro Okunushi Hanae Morio Tomomi Furihata Naohiko Anzai Tadahiko Mashino 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3708-3711
We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR. 相似文献
88.
89.
Masaru Tateno Kazuhiko Yamasaki Naoki Amano Jun Kakinuma Hideaki Koike Mark D. Allen Masashi Suzuki 《Biopolymers》1997,44(4):335-359
The modes of DNA recognition by β-sheets are analyzed by using the known crystal and solution three-dimensional structures of DNA-protein complexes. Close fitting of the protein surface and the DNA surface determines the binding geometry. Interaction takes place so that essentially the N-to-C direction of the β-strands either follows or crosses the DNA groove. Upon following the major groove a two-stranded antiparallel β-sheet dives into the groove and contacts DNA bases with its convex side facing the DNA, while upon following the minor groove, it binds around the sugar-phosphate backbones, with its opposite concave side shielding the DNA. In order for the β-strands crossing the minor groove to interact with the DNA, the dinucleotide steps need to almost totally helically untwist and roll around major groove. The β-sheet, on the other hand, needs to adopt a concave curvature on the binding surface in the direction that follows the DNA minor groove, and a convex surface in the direction that bridges the sugar-phosphate backbones across the groove. The result is to produce a hyperbolic paraboloidal DNA-binding surface. © 1998 John Wiley & Sons, Inc. Biopoly 44: 335–359, 1997 相似文献
90.
Shimazu M Sekito T Akiyama K Ohsumi Y Kakinuma Y 《The Journal of biological chemistry》2005,280(6):4851-4857
Among the members of the major facilitator superfamily of Saccharomyces cerevisiae, we identified genes involved in the transport into vacuoles of the basic amino acids histidine, lysine, and arginine. ATP-dependent uptake of histidine and lysine by isolated vacuolar membrane vesicles was impaired in YMR088c, a vacuolar basic amino acid transporter 1 (VBA1)-deleted strain, whereas uptake of tyrosine or calcium was little affected. This defect in histidine and lysine uptake was complemented fully by introducing the VBA1 gene and partially by a gene encoding Vba1p fused with green fluorescent protein, which was determined to localize exclusively to the vacuolar membrane. A defect in the uptake of histidine, lysine, or arginine was also observed in the vacuolar membrane vesicles of mutants YBR293w (VBA2) and YCL069w (VBA3). These three VBA genes are closely related phylogenetically and constitute a new family of basic amino acid transporters in the yeast vacuole. 相似文献