Investigation of abnormal cytokine signaling and the development of the drugs modulating these signaling

异常细胞因子信号传导的研究以及调节这些信号传导的药物的开发

• 批准号: 21590072
• 负责人: KASAHARA Tadashi
• 金额: $ 3万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590072/
• 关键词: 接着班キナーゼFAK; JAKキナーゼ; JAK2 V617F変異体; Epoシグナル; STAT5の恒常的な活性化; 腫瘍形成能; リコカルコンA; JAK2点変異V617F; JAK2シグナル伝達; STAT5; c-Myc; GSK-3β; メラノーマ細胞; 抗アポトーシス因子; GSK-3βのリン酸化; NF-κB阻害作用; 接着分子FAK; JAK2; チロシンリン酸化; V617F変異体; 真性赤血球増加症

(1) We previously reported that a FAKY929F mutant in the B16F10 melanoma cell line gave poor metastasis. Here, we identified that the phospholipid protein(PLP) 2 was downregulated in this cell line, acting as an effector molecule downstream of FAK. Why PLP2 induces the metastatic activity was investigated in vitro and in vivo.(2) A JAK2 mutant, JAK2V617F was constitutively active and induced abnormal proliferation, tumorigenesis in nude mice, as well as exhibited resistance to antitumor drugs including cisplatin. The reason why JAK2V617F has such potent activities was studied. We presented a notion that JAK2 mutation constitutively activated STAT5, which enhanced various transcription factors and kinases including c-Myc, Aurora kinaseA or Pim-1/2, thus inducing transformation in vitro and in vivo.

(1)我们之前报道过B16F10黑色素瘤细胞系中的FAKY929F突变体转移不良。在这里，我们发现磷脂蛋白（PLP） 2在该细胞系中下调，作为FAK下游的效应分子。在体外和体内研究PLP2诱导转移活性的原因。(2) JAK2突变体JAK2V617F在裸鼠体内具有组成性活性，可诱导异常增殖和肿瘤发生，并对顺铂等抗肿瘤药物产生耐药性。研究了JAK2V617F具有如此强效活性的原因。我们提出JAK2突变组成性激活STAT5，从而增强多种转录因子和激酶，包括c-Myc， Aurora kinaseA或Pim-1/2，从而诱导体外和体内转化。

项目成果

4P-221真性赤血球増加症由来JAK2点変異(V617F)によるアポトーシス耐性機構の解析

4P-221真性红细胞增多症源性JAK2点突变(V617F)诱导的细胞凋亡抵抗机制分析

• 发表时间: 2009
• 作者: 上四元純;多胡めぐみ;園田よし子;笠原忠
• 通讯作者: 笠原忠

Licochalcones suppress degranulation by decreasing the intracellular Ca2+ level and tyrosine phosphorylation of ERK in RBL-2H3 cells.

• DOI: 10.1016/j.intimp.2010.04.007
• 发表时间: 2010-07
• 期刊: International immunopharmacology
• 影响因子: 5.6
• 作者: Shota Tanifuji;E. Aizu-Yokota;M. Funakoshi-Tago;Y. Sonoda;H. Inoue;T. Kasahara

The Acute Lymphoblastic Leukemia-associated JAK2 L611S Mutant Induces Tumorigenesis in Nude Mice

• DOI: 10.1074/jbc.m808879200
• 发表时间: 2009-05-08
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Funakoshi-Tago, Megumi;Tago, Kenji;Kasahara, Tadashi
• 通讯作者: Kasahara, Tadashi

JAK2 is an important signal transducer in IL-33-induced NF-χB activation

JAK2 是 IL-33 诱导的 NF-χB 激活中重要的信号转导因子

• 发表时间: 2011
• 期刊: Cell Signaling
• 作者: Funakoshi-Tago M;Tago K;Sato Y;Tominaga S;Kasahara T
• 通讯作者: Kasahara T

TNFαシグナル伝達に及ぼす Flavonoid 化合物の影響

黄酮类化合物对 TNFα 信号传导的影响

• 发表时间: 2010
• 作者: 中村慶;多胡めぐみ;園田よし子;笠原忠
• 通讯作者: 笠原忠