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| 1.
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論文
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Funasaka, Tatsuyoshi ; Nakano, Hiroshi ; Wu, Yu ; Hashizume, Chieko ; Gu, Ling ; Nakamura, Takuro ; Wang, Wei ; Zhou, Pengbo ; Moore, Malcolm AS ; Sato, Hiroshi ; Wong, Richard W.
概要:
金沢大学フロンティアサイエンス機構<br />Chromosomal translocations involving chimeric fusions of the nucleoporin NUP98 protein have often
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been described in acute myelogenous leukemia (AML). All the fusion proteins have an identical NUP98 N terminus, which contains the GLEBS motif for interaction with the mRNA export factor RAE1 and FG repeats that associate with the transcription factors HDAC1 and p300. It is virtually unknown whether these interaction partners affect leukemogenesis. We previously showed that RAE1 depletion caused aneuploidy, which enhanced tumorigenesis. We speculated that RAE1 may also be directly involved in NUP98 fusion-mediated leukemogenesis. We show here that RNA interference (RNAi)-mediated knockdown of NUP98 caused severe chromosome segregation defects and disrupted RAE1 but not HDAC1 expression and localization. Next, we performed rescue experiments to confirm that the RAE1-NUP98 complex orchestrates proper chromosome segregation. Interestingly, we found diverse behaviors of NUP98 and the leukemogenic fusion protein NUP98-HOXA9 throughout the cell cycle. Strikingly, in NUP98-HOXA9-transfected cells, RAE1 protein were reduced and mis-localized. Our cellular interpretations were further confirmed by NUP98-HOXA9 transgenic mice and the NUP98-HOXA9 AML patient. These data suggest that RAE1 orchestrates NUP98-mediated leukemogenesis and raise the possibility that targeting this negative feedback loop may provide a new strategy for the therapy of aggressive leukemias. © 2011 Landes Bioscience.
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| 2.
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Popivanova, Boryana K. ; Kitamura, Kazuya ; Wu, Yu ; Kondo, Toshikazu ; Kagaya, Takashi ; Kaneko, Shuichi ; Oshima, Masanobu ; Fujii, Chifumi ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To un
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derstand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-α expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-α, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-α as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-α may be useful in treating colon cancer in individuals with UC.
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| 3.
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Wu, Yu ; Wang, Ying Ying ; Nakamoto, Yasunari ; Li, Ying-Yi ; Baba, Tomohisa ; Kaneko, Shuichi ; Fujii, Chifumi ; Mukaida, Naofumi
概要:
金沢大学がん研究所<br />Pim-3, a proto-oncogene with serine/threonine kinase activity, was enhanced in hepatocellular carcinoma (
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HCC) tissues. To address the roles of Pim-3 in HCC development, we prepared transgenic mice that express human Pim-3 selectively in liver. The mice were born at a Mendelian ratio, were fertile and did not exhibit any apparent pathological changes in the liver until 1 year after birth. Pim-3-transgenic mouse-derived hepatocytes exhibited accelerated cell cycle progression. The administration of a potent hepatocarcinogen, diethylnitrosamine (DEN), induced accelerated proliferation of liver cells in Pim-3 transgenic mice in the early phase, compared with that observed for wild-type mice. Treatment with DEN induced lipid droplet accumulation with increased proliferating cell numbers 6 months after the treatment. Eventually, wild-type mice developed HCC with a frequency of 40% until 10 month after the treatment. Lipid accumulation was accelerated in Pim-3 transgenic mice with higher proliferating cell numbers, compared with that observed for wild-type mice. Pim-3 transgenic mice developed HCC with a higher incidence (80%) and a heavier burden, together with enhanced intratumoral CD31-positive vascular areas, compared with that observed for wild-type mice. These observations indicate that Pim-3 alone cannot cause, but can accelerate HCC development when induced by a hepatocarcinogen, such as DEN. © 2010 Macmillan Publishers Limited. All rights reserved.
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| 4.
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Iida, Noriho ; Nakamoto, Yasunari ; Baba, Tomohisa ; Kakinoki, Kaheita ; Li, Ying-Yi ; Wu, Yu ; Matsushita, Kouji ; Kaneko, Shuichi ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />The first step in the generation of tumor immunity is the migration of dendritic cells (DCs) to the
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apoptotic tumor, which is presumed to be mediated by various chemokines. To clarify the roles of chemokines, we induced apoptosis using suicide gene therapy and investigated the immune responses following tumor apoptosis. We injected mice with a murine hepatoma cell line, BNL 1ME A.7R.1 (BNL), transfected with HSV-thymidine kinase (tk) gene and then treated the animals with ganciclovir (GCV). GCV treatment induced massive tumor cell apoptosis accompanied with intratumoral DC infiltration. Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Moreover, tumor apoptosis increased the numbers of DCs migrating into the draining lymph nodes and eventually generated a specific cytotoxic cell population against BNL cells. Although GCV completely eradicated HSV-tk-transfected BNL cells in CCR1-, CCR5-, or CCL3-deficient mice, intratumoral and intranodal DC infiltration and the subsequent cytotoxicity generation were attenuated in these mice. When parental cells were injected again after complete eradication of primary tumors by GCV treatment, the wild-type mice completely rejected the rechallenged cells, but the deficient mice exhibited impairment in rejection. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes. © Society for Leukocyte Biology.全文公開200910
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Li, Ying-Yi ; Wu, Yu ; Tsuneyama, Koichi ; Baba, Tomohisa ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />We previously demonstrated that the proto-oncogene Pim-3 with serine/ threonine kinase activity was
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aberrantly expressed in cancer cells but not in the normal cells of the pancreas. In order to elucidate the molecular mechanism underlying aberrant Pim-3 expression in pancreatic cancer cells, we constructed luciferase expression vectors linked to 5′-flanking deletion mutants of the human Pim-3 gene and transfected human pancreatic cancer cells with the resultant vectors. The region up to -264 bp was essential for constitutive Pim-3 gene expression, and the mutation in the Ets-1 binding site (between -216 and -211 bp) reduced luciferase activities. Moreover, Ets-1 mRNA and protein were constitutively expressed together with Pim-3 in human pancreatic cancer cell lines. Chromatin immunoprecipitation assay demonstrated constitutive binding of Ets-1 to the 5′-flanking region of human Pim-3 gene between -249 and -183 bp. Pim-3 promoter activity and its protein expression were induced by transfection with wild type-Ets-1 and were reduced by transfection with dominant negative-Ets-1 or Ets-1 small-interfering RNA (siRNA). Furthermore, dominant negative-Ets-1 and Ets-1 siRNA reduced the amount of Bad phosphorylated at its Ser 112 and induced apoptosis, when they were transfected into human pancreatic cancer cells. Finally, Pim-3 cDNA transfection reversed Ets-1 siRNA-induced increase in apoptosis and decrease in Bad phosphorylation at its Ser 112. These observations would indicate that the transcription factor Ets-1 can induce aberrant Pim-3 expression and subsequently prevent apoptosis in human pancreatic cancer cells. © 2009 Japanese Cancer Association.
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| 6.
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Wu, Yu ; Baba, T. ; Mukaida, Naofumi
概要:
Division of Molecular Bioregulation
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| 7.
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Popivanova, Boryana K. ; Kitamura, Kazuya ; Wu, Yu ; Kondo, Toshikazu ; Kagaya, Takashi ; Kaneko, Shuichi ; Oshima, Masanobu ; Fujii, Chifurni ; Mukaida, Naofumi ; 北村, 和哉 ; 近藤, 稔和 ; 加賀谷, 尚史 ; 金子, 周一 ; 大島, 正伸 ; 向田, 直史
概要:
金沢大学がん進展制御研究所<br />The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To unde
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rstand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-α expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-α, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-α as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-α may be useful in treating colon cancer in individuals with UC.
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