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971.
Tomonari Takemura Satoki Nakamura Daisuke Yokota Isao Hirano Takaaki Ono Kazuyuki Shigeno Shinya Fujisawa Kazunori Ohnishi 《The Journal of biological chemistry》2010,285(9):6585-6594
Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. The Ras/Raf-1/MEK/ERK pathway is constitutively activated in Bcr-Abl-transformed cells, and Ras activity enhances the oncogenic ability of Bcr-Abl. However, the mechanism by which Bcr-Abl activates the Ras pathway is not completely understood. Raf kinase inhibitor protein (RKIP) inhibits activation of MEK by Raf-1 and its downstream signal transduction, resulting in blocking the MAP kinase pathway. In the present study, we found that RKIP was depleted in CML cells. We investigated the interaction between RKIP and Bcr-Abl in CML cell lines and Bcr-Abl+ progenitor cells from CML patients. The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of RKIP and reduced the pERK1/2 status, resulting in inhibited proliferation of CML cells. Moreover, RKIP up-regulated cell cycle regulator FoxM1 expression, resulting in G1 arrest via p27Kip1 and p21Cip1 accumulation. In colony-forming unit granulocyte, erythroid, macrophage, megakaryocyte, colony-forming unit-granulocyte macrophage, and burst-forming unit erythroid, treatment with the Abl kinase inhibitors and depletion of Bcr-Abl induced RKIP and reduced FoxM1 expressions, and inhibited colony formation of Bcr-Abl+ progenitor cells, whereas depletion of RKIP weakened the inhibition of colony formation activity by the Abl kinase inhibitors in Bcr-Abl+ progenitor cells. Thus, Bcr-Abl represses the expression of RKIP, continuously activates pERK1/2, and suppresses FoxM1 expression, resulting in proliferation of CML cells. 相似文献
972.
Jimmy D. Dikeakos Katelyn M. Atkins Laurel Thomas Lori Emert-Sedlak In-Ja L. Byeon Jinwon Jung Jinwoo Ahn Matthew D. Wortman Ben Kukull Masumichi Saito Hirokazu Koizumi Danielle M. Williamson Masateru Hiyoshi Eric Barklis Masafumi Takiguchi Shinya Suzu Angela M. Gronenborn Thomas E. Smithgall Gary Thomas 《Molecular biology of the cell》2010,21(19):3279-3292
HIV-1 Nef triggers down-regulation of cell-surface MHC-I by assembling a Src family kinase (SFK)-ZAP-70/Syk-PI3K cascade. Here, we report that chemical disruption of the Nef-SFK interaction with the small molecule inhibitor 2c blocks assembly of the multi-kinase complex and represses HIV-1–mediated MHC-I down-regulation in primary CD4+ T-cells. 2c did not interfere with the PACS-2–dependent trafficking of Nef required for the Nef-SFK interaction or the AP-1 and PACS-1–dependent sequestering of internalized MHC-I, suggesting the inhibitor specifically interfered with the Nef-SFK interaction required for triggering MHC-I down-regulation. Transport studies revealed Nef directs a highly regulated program to down-regulate MHC-I in primary CD4+ T-cells. During the first two days after infection, Nef assembles the 2c-sensitive multi-kinase complex to trigger down-regulation of cell-surface MHC-I. By three days postinfection Nef switches to a stoichiometric mode that prevents surface delivery of newly synthesized MHC-I. Pharmacologic inhibition of the multi-kinase cascade prevents the Nef-dependent block in MHC-I transport, suggesting the signaling and stoichiometric modes are causally linked. Together, these studies resolve the seemingly controversial models that describe Nef-induced MHC-I down-regulation and provide new insights into the mechanism of Nef action. 相似文献
973.
974.
975.
Etsushi Kitamura Kozo Tanaka Shinya Komoto Yoko Kitamura Claude Antony Tomoyuki U. Tanaka 《Developmental cell》2010,18(2):248-259
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976.
Hirotaka Imai Kyoko Shinya Ryo Takano Maki Kiso Yukiko Muramoto Saori Sakabe Shin Murakami Mutsumi Ito Shinya Yamada Mai thi Quynh Le Chairul A. Nidom Yuko Sakai-Tagawa Kei Takahashi Yasuyuki Omori Takeshi Noda Masayuki Shimojima Satoshi Kakugawa Hideo Goto Kiyoko Iwatsuki-Horimoto Taisuke Horimoto Yoshihiro Kawaoka 《PLoS pathogens》2010,6(9)
Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. 相似文献
977.
978.
Umeda T Takashima N Nakagawa R Maekawa M Ikegami S Yoshikawa T Kobayashi K Okanoya K Inokuchi K Osumi N 《PloS one》2010,5(12):e15500
Autism is a highly variable brain developmental disorder and has a strong genetic basis. Pax6 is a pivotal player in brain development and maintenance. It is expressed in embryonic and adult neural stem cells, in astrocytes in the entire central nervous system, and in neurons in the olfactory bulb, amygdala, thalamus, and cerebellum, functioning in highly context-dependent manners. We have recently reported that Pax6 heterozygous mutant (rSey(2)/+) rats with a spontaneous mutation in the Pax6 gene, show impaired prepulse inhibition (PPI). In the present study, we further examined behaviors of rSey(2)/+ rats and revealed that they exhibited abnormality in social interaction (more aggression and withdrawal) in addition to impairment in rearing activity and in fear-conditioned memory. Ultrasonic vocalization (USV) in rSey(2)+ rat pups was normal in male but abnormal in female. Moreover, treatment with clozapine successfully recovered the defects in sensorimotor gating function, but not in fear-conditioned memory. Taken together with our prior human genetic data and results in other literatures, rSey(2)/+ rats likely have some phenotypic components of autism. 相似文献
979.
Yu-ichi Ozaki Shinsuke Uda Takeshi H. Saito Jaehoon Chung Hiroyuki Kubota Shinya Kuroda 《PloS one》2010,5(4)
Background
Modeling of cellular functions on the basis of experimental observation is increasingly common in the field of cellular signaling. However, such modeling requires a large amount of quantitative data of signaling events with high spatio-temporal resolution. A novel technique which allows us to obtain such data is needed for systems biology of cellular signaling.Methodology/Principal Findings
We developed a fully automatable assay technique, termed quantitative image cytometry (QIC), which integrates a quantitative immunostaining technique and a high precision image-processing algorithm for cell identification. With the aid of an automated sample preparation system, this device can quantify protein expression, phosphorylation and localization with subcellular resolution at one-minute intervals. The signaling activities quantified by the assay system showed good correlation with, as well as comparable reproducibility to, western blot analysis. Taking advantage of the high spatio-temporal resolution, we investigated the signaling dynamics of the ERK pathway in PC12 cells.Conclusions/Significance
The QIC technique appears as a highly quantitative and versatile technique, which can be a convenient replacement for the most conventional techniques including western blot, flow cytometry and live cell imaging. Thus, the QIC technique can be a powerful tool for investigating the systems biology of cellular signaling. 相似文献980.
Toshitaka Okabayashi Kuniaki Nakanishi Toyokazu Tsuchihara Hiroshi Arino Yasuo Yoshihara Susumu Tominaga Maki Uenoyama Shinya Suzuki Masataka Asagiri Koichi Nemoto 《PloS one》2010,5(9)