Molecular mechanisms of abnormal differentiation and transcriptional regulation in cancer cel

癌细胞异常分化和转录调控的分子机制

• 批准号: 17014017
• 负责人: INOUE Jun-ichiro
• 金额: $ 32.13万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17014017/
• 关键词: 癌; シグナル伝達; 発現制御; 発生・分化; ウイルス発癌; ウィルス発癌; 発生制御; 白血病; NFκB; TRAF6; HTLV-1; Tax

We aimed to clarify molecular mechanisms of the TRAF6-mediated NF-κB activation and roles of NF-κB in oncogenesis and malignancy. The following results were obtained. (1)Oncogenic Tax protein of HTLV-1 activates NF-κB to induce dysregulated cell growth. In contrast to the cytokine-induced NF-κB activation, our results strongly suggest that Tax-mediated NF-κB activation does not require TAK1 and K63-linked polyubiquitination of NEMO. Based on these results we propose a novel model of NF-κB activation by Tax. (2)Enhanced expression of IL-1 is involved in malignancy of cancer. We found that IL-1 stimulation results in TRAF6-catalyzed K63-linked polyubiquitination of TAK1, which is essential for TAK1 activation. We further found that MEKK3 is an essential upstream activator of TAK1, and TRAF6, MEKK3 and TAK1 form signal complexes in an IL-1 stimulation-dependent manner. We propose the biphasic NF-κB activation model, in which the TAK1-dependent RING pathway precedes the TAK1-independent Zinc pathway. (3)We identified 25 NF-κB target genes that probably involved in cancer malignancy. (4)Six cell lines derived from breast, lung and gastric cancers, whose growth depends on NF-kB activation, grow in an IKKα-dependent manner. The result suggests involvement of the non-classical pathway in their proliferation.

我们旨在阐明TRAF6介导的NF-κB激活的分子机制以及NF-κB在肿瘤发生和恶性肿瘤中的作用。获得以下结果。 （1）HTLV-1的致癌税蛋白激活NF-κB以诱导失调的细胞生长。与细胞因子诱导的NF-κB激活相反，我们的结果强烈表明，税收介导的NF-κB激活不需要NEMO的TAK1和K63连接的多泛素化。基于这些结果，我们提出了一种通过税收激活NF-κB激活的新型模型。 （2）IL-1的表达增强参与癌症的恶性肿瘤。我们发现IL-1模拟导致TRAF6催化的K63连接的TAK1的多泛素化，这对于TAK1激活至关重要。我们进一步发现，Mekk3是TAK1的必不可少的上游激活因子，而TRAF6，MEKK3和TAK1以IL-1模拟依赖性方式形成了信号复合物。我们提出了双相NF-κB激活模型，其中tak1依赖性环途径在独立于tak1的锌途径之前。 （3）我们确定了可能涉及癌症恶性肿瘤的25个NF-κB靶基因。 （4）以IKKα依赖性方式生长的乳腺癌，肺和胃癌的六个细胞系，其生长取决于NF-KB的活化。结果表明非古典途径参与其增殖。

项目成果

Signaling Flux Redistribution at Toll-Like Receptor Pathway Junctions

• DOI: 10.1371/journal.pone.0003430
• 发表时间: 2008-10-17
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Selvarajoo, Kumar;Takada, Yasunari;Matsuo, Koichi
• 通讯作者: Matsuo, Koichi

Human lactoferrin activates NF-κB through Toll-like receptor 4(TLR4)pathway while it interferes with the lipopolysaccharide-stimulated TLR4 signaling

人乳铁蛋白通过 Toll 样受体 4 (TLR4) 途径激活 NF-κB，同时干扰脂多糖刺激的 TLR4 信号传导

• 发表时间: 2010
• 期刊: FEBS Journal (in press)
• 作者: Ando;K.
• 通讯作者: K.

Characteristics and Biological Functions of TRAF6. In "TRAFs" edited by Hao Wu.

TRAF6的特性和生物学功能。

• 发表时间: 2006
• 期刊: Landes Bioscience, Adv Exp Med Biol 597
• 作者: Inoue;J.;Gohda;J.;Akiyama;T.
• 通讯作者: T.

疾患メカニズムの解明に向けたチロシンリン酸化ネットワークに関する包括的動態解析

酪氨酸磷酸化网络的综合动态分析阐明疾病机制

• 发表时间: 2007
• 作者: 松村隆之;井上純一郎;茂木秀彦;山崎孔輔;山口憲孝;尾山大明
• 通讯作者: 尾山大明

TNF-receptor associated factor 6-deficient fibroblast is sensitive to the TNF-alpha-induced cell death: Involvement of reactive oxygen species.

TNF 受体相关因子 6 缺陷的成纤维细胞对 TNF-α 诱导的细胞死亡敏感：活性氧的参与。

• 发表时间: 2006
• 期刊: Biochem Biophys Res Commun. 351
• 作者: Ichikawa;D.;Funakoshi-Tago;M.;Aizu-Yokota;E.;Sonoda;Y.;Inoue;J.;Kasahara T.
• 通讯作者: Kasahara T.