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961.
Takeshi Harada Shuji Ozaki Asuka Oda Daisuke Tsuji Akishige Ikegame Masami Iwasa Kengo Udaka Shiro Fujii Shingen Nakamura Hirokazu Miki Kumiko Kagawa Yoshiaki Kuroda Shigeto Kawai Kohji Itoh Hisafumi Yamada-Okabe Toshio Matsumoto Masahiro Abe 《PloS one》2013,8(12)
The immunomodulatory drug lenalidomide (Len) has drawn attention to potentiate antibody-dependent cellular cytotoxicity (ADCC)-mediated immunotherapies. We developed the defucosylated version (YB-AHM) of humanized monoclonal antibody against HM1.24 (CD317) overexpressed in multiple myeloma (MM) cells. In this study, we evaluated ADCC by YB-AHM and Len in combination against MM cells and their progenitors. YB-AHM was able to selectively kill via ADCC MM cells in bone marrow samples from patients with MM with low effector/target ratios, which was further enhanced by treatment with Len. Interestingly, Len also up-regulated HM1.24 expression on MM cells in an effector-dependent manner. HM1.24 was found to be highly expressed in a drug-resistant clonogenic “side population” in MM cells; and this combinatory treatment successfully reduced SP fractions in RPMI 8226 and KMS-11 cells in the presence of effector cells, and suppressed a clonogenic potential of MM cells in colony-forming assays. Collectively, the present study suggests that YB-AHM and Len in combination may become an effective therapeutic strategy in MM, warranting further study to target drug-resistant MM clonogenic cells. 相似文献
962.
Hideaki Yamamoto Tomohiko Maruo Takashi Majima Hiroyoshi Ishizaki Miki Tanaka-Okamoto Jun Miyoshi Kenji Mandai Yoshimi Takai 《PloS one》2013,8(11)
Adherens junctions (AJs) play a role in mechanically connecting adjacent cells to maintain tissue structure, particularly in epithelial cells. The major cell–cell adhesion molecules at AJs are cadherins and nectins. Afadin binds to both nectins and α-catenin and recruits the cadherin-β-catenin complex to the nectin-based cell–cell adhesion site to form AJs. To explore the role of afadin in radial glial and ependymal cells in the brain, we generated mice carrying a nestin-Cre-mediated conditional knockout (cKO) of the afadin gene. Newborn afadin-cKO mice developed hydrocephalus and died neonatally. The afadin-cKO brain displayed enlarged lateral ventricles and cerebral aqueduct, resulting from stenosis of the caudal end of the cerebral aqueduct and obliteration of the ventral part of the third ventricle. Afadin deficiency further caused the loss of ependymal cells from the ventricular and aqueductal surfaces. During development, radial glial cells, which terminally differentiate into ependymal cells, scattered from the ventricular zone and were replaced by neurons that eventually covered the ventricular and aqueductal surfaces of the afadin-cKO midbrain. Moreover, the denuded ependymal cells were only occasionally observed in the third ventricle and the cerebral aqueduct of the afadin-cKO midbrain. Afadin was co-localized with nectin-1 and N-cadherin at AJs of radial glial and ependymal cells in the control midbrain, but these proteins were not concentrated at AJs in the afadin-cKO midbrain. Thus, the defects in the afadin-cKO midbrain most likely resulted from the destruction of AJs, because AJs in the midbrain were already established before afadin was genetically deleted. These results indicate that afadin is essential for the maintenance of AJs in radial glial and ependymal cells in the midbrain and is required for normal morphogenesis of the cerebral aqueduct and ventral third ventricle in the midbrain. 相似文献
963.
Akira Isogai Naoyuki Fukuchi Miki Hayashi Hiroshi Kamada Hiroshi harada Akinori Suzuki 《Bioscience, biotechnology, and biochemistry》2013,77(12):3235-3237
A enzyme that catalyzed the specific formation of ascorbic acid-2-phosphate (AsA2P) from ascorbic acid (AsA) and adenosine-5′-triphosphate (ATP), was purified 3,200-fold to homogeneity from a cell extract of Pseudomonas azotocolligans. The purified enzyme appeared as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and consisted of a single polypeptide with a molecular weight of about 30,000. Of phosphoryl donors tested, p-nitrophenylphosphate (p-NPP) and pyrophosphate (PPi) were as effective as ATP. Optimal pHs for the phosphorylating activity were around 4.0 and 5.5 when PPi and ATP were used as phosphoryl donors, respectively. The Km for AsA was 147 mm. The enzyme activity was inhibited by Cu2+, but not by sulfhydryl reagents.The enzyme simultaneously had phosphatase activity at weakly acidic or neutral pH and the Km for p-NPP in the phosphatase activity was 0.38 mm. The enzyme was tentatively named “ascorbic acid phosphorylating enzyme.” 相似文献
964.
Toyomi Yamazaki Miki Sagisaka Riko Ikeda Toshiyuki Nakamura Noriko Matsuda Takeshi Ishii 《Bioscience, biotechnology, and biochemistry》2013,77(10):1753-1756
We purified several hundred mgs of four major theaflavins (theaflavin, theaflavin-3-O-gallate, theaflavin-3′-O-gallate, and theaflavin-3,3′-O-digallate). Among the 25 hTAS2Rs expressed in HEK293T cells, hTAS2R39 and hTAS2R14 were activated by theaflavins. Both hTAS2R39 and hTAS2R14 responded to theaflavin-3′-O-gallate. In addition, hTAS2R39 was activated by theaflavin and theaflavin-3,3′-O-gallate, but not by theaflavin-3-O-gallate. In contrast, hTAS2R14 responded to theaflavin-3-O-gallate. 相似文献
965.
Naoki Tomita Yoko Hayashi Shinkichi Suzuki Yoshimasa Oomori Yoshio Aramaki Yoshihiro Matsushita Misa Iwatani Hidehisa Iwata Atsutoshi Okabe Yoshiko Awazu Osamu Isono Robert J. Skene David J. Hosfield Hiroshi Miki Tomohiro Kawamoto Akira Hori Atsuo Baba 《Bioorganic & medicinal chemistry letters》2013,23(6):1779-1785
In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50 = 0.64 μM) and in cellular assays (IC50 = 7.1 μM). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents. 相似文献
966.
Murakami M Taketomi Y Miki Y Sato H Hirabayashi T Yamamoto K 《Progress in lipid research》2011,50(2):152-192
Mammalian genomes encode genes for more than 30 phospholipase A2s (PLA2s) or related enzymes, which are subdivided into several classes including low-molecular-weight secreted PLA2s (sPLA2s), Ca2+-dependent cytosolic PLA2s (cPLA2s), Ca2+-independent PLA2s (iPLA2s), platelet-activating factor acetylhydrolases (PAF-AHs), lysosomal PLA2s, and a recently identified adipose-specific PLA. Of these, the intracellular cPLA2 and iPLA2 families and the extracellular sPLA2 family are recognized as the “big three”. From a general viewpoint, cPLA2α (the prototypic cPLA2) plays a major role in the initiation of arachidonic acid metabolism, the iPLA2 family contributes to membrane homeostasis and energy metabolism, and the sPLA2 family affects various biological events by modulating the extracellular phospholipid milieus. The cPLA2 family evolved along with eicosanoid receptors when vertebrates first appeared, whereas the diverse branching of the iPLA2 and sPLA2 families during earlier eukaryote development suggests that they play fundamental roles in life-related processes. During the past decade, data concerning the unexplored roles of various PLA2 enzymes in pathophysiology have emerged on the basis of studies using knockout and transgenic mice, the use of specific inhibitors, and information obtained from analysis of human diseases caused by mutations in PLA2 genes. This review focuses on current understanding of the emerging biological functions of PLA2s and related enzymes. 相似文献
967.
Himuro Y Tanaka H Hashiguchi M Ichikawa T Nakazawa M Seki M Fujita M Shinozaki K Matsui M Akashi R Hoffmann F 《Journal of plant physiology》2011,168(2):181-187
Using the full-length cDNA overexpressor (FOX) gene-hunting system, we have generated 130 Arabidopsis FOX-superroot lines in bird's-foot trefoil (Lotus corniculatus) for the systematic functional analysis of genes expressed in roots and for the selection of induced mutants with interesting root growth characteristics. We used the Arabidopsis-FOX Agrobacterium library (constructed by ligating pBIG2113SF) for the Agrobacterium-mediated transformation of superroots (SR) and the subsequent selection of gain-of-function mutants with ectopically expressed Arabidopsis genes. The original superroot culture of L. corniculatus is a unique host system displaying fast root growth in vitro, allowing continuous root cloning, direct somatic embryogenesis and mass regeneration of plants under entirely hormone-free culture conditions. Several of the Arabidopsis FOX-superroot lines show interesting deviations from normal growth and morphology of roots from SR-plants, such as differences in pigmentation, growth rate, length or diameter. Some of these mutations are of potential agricultural interest. Genomic PCR analysis revealed that 100 (76.9%) out of the 130 transgenic lines showed the amplification of single fragments. Sequence analysis of the PCR fragments from these 100 lines identified full-length cDNA in 74 of them. Forty-three out of 74 full-length cDNA carried known genes. The Arabidopsis FOX-superroot lines of L. corniculatus, produced in this study, expand the FOX hunting system and provide a new tool for the genetic analysis and control of root growth in a leguminous forage plant. 相似文献
968.
Staerk J Defour JP Pecquet C Leroy E Antoine-Poirel H Brett I Itaya M Smith SO Vainchenker W Constantinescu SN 《The EMBO journal》2011,30(21):4398-4413
Ligand binding to the thrombopoietin receptor is thought to stabilize an active receptor dimer that regulates megakaryocyte differentiation and platelet formation, as well as haematopoietic stem cell renewal. By fusing a dimeric coiled coil in all seven possible orientations to the thrombopoietin receptor transmembrane (TM)-cytoplasmic domains, we show that specific biological effects and in vivo phenotypes are imparted by distinct dimeric orientations, which can be visualized by cysteine mutagenesis and crosslinking. Using functional assays and computational searches, we identify one orientation that represents the inactive dimeric state and another similar to a physiologically activated receptor. Several other dimeric orientations are identified that induce proliferation and in vivo myeloproliferative and myelodysplastic disorders, indicating the receptor can signal from several dimeric interfaces. The set of dimeric thrombopoietin receptors with different TM orientations may offer new insights into the activation of distinct signalling pathways by a single receptor and suggests that subtle differences in cytokine receptor dimerization provide a new layer of signalling regulation that is relevant for disease. 相似文献
969.
970.
Cortical microtubules optimize cell-wall crystallinity to drive unidirectional growth in Arabidopsis
Fujita M Himmelspach R Hocart CH Williamson RE Mansfield SD Wasteneys GO 《The Plant journal : for cell and molecular biology》2011,66(6):915-928
The shape of plants depends on cellulose, a biopolymer that self-assembles into crystalline, inextensible microfibrils (CMFs) upon synthesis at the plasma membrane by multi-enzyme cellulose synthase complexes (CSCs). CSCs are displaced in directions predicted by underlying parallel arrays of cortical microtubules, but CMFs remain transverse in cells that have lost the ability to expand unidirectionally as a result of disrupted microtubules. These conflicting findings suggest that microtubules are important for some physico-chemical property of cellulose that maintains wall integrity. Using X-ray diffraction, we demonstrate that abundant microtubules enable a decrease in the degree of wall crystallinity during rapid growth at high temperatures. Reduced microtubule polymer mass in the mor1-1 mutant at high temperatures is associated with failure of crystallinity to decrease and a loss of unidirectional expansion. Promotion of microtubule bundling by over-expressing the RIC1 microtubule-associated protein reduced the degree of crystallinity. Using live-cell imaging, we detected an increase in the proportion of CSCs that track in microtubule-free domains in mor1-1, and an increase in the CSC velocity. These results suggest that microtubule domains affect glucan chain crystallization during unidirectional cell expansion. Microtubule disruption had no obvious effect on the orientation of CMFs in dark-grown hypocotyl cells. CMFs at the outer face of the hypocotyl epidermal cells had highly variable orientation, in contrast to the transverse CMFs on the radial and inner periclinal walls. This suggests that the outer epidermal mechanical properties are relatively isotropic, and that axial expansion is largely dependent on the inner tissue layers. 相似文献