Regulatory mechanism of cell growth and differentiation by genes related to cancers

癌症相关基因对细胞生长和分化的调控机制

基本信息

批准号：
12219207
负责人：
MATSUMOTO Kunihiro
金额：
$ 139.71万
依托单位：
Nagoya University
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：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

Chronic inflammation is responsible for the development of many human cancers. Proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin 1 (IL-1), activate the transcription of genes encoding chemokines, cytokines, cell survival factors, growth factors involved in angiogenesis and reactive oxygen species, which are thought to influence the cancer pathology. TNF and IL-1 initiate the cell signaling by binding to their receptors and lead to activate two major transcription factors, NF-kB and AP1, which mediate most of the transcriptional activation. The signaling mechanism proximal either to receptors or to transcription factors had been extensively studies for past ten years. However, our understanding of the signaling intermediates between receptor complexes and the transcription factors remained incomplete. In this project, we have identified that TAK1 MAPKKK is an essential intermediate of TNF/IL-1 signaling pathway linking the receptor to downstream effectors. TAK1 is activated upon TNF and IL-1 treatment to the cells, and then stimulate MAPK cascade and IkB kinase pathways, which ultimately activate API and NF-kB, respectively. We have also isolated TAB2 and TAB3 as TAK1 binding partners, and demonstrated that TAB2 and TAB3 function as adaptors linking TAK1 to the receptor complexes. TAB2 and TAB3 are essential for TAK1 activated by TNF/IL-1. These findings provide potential new therapeutic targets to inhibit inflammatory response as well as tumor progression in chronic inflammatory diseases.

慢性炎症是许多人类癌症的发展。促炎细胞因子，肿瘤坏死因子（TNF）和白介素1（IL-1）激活编码趋化因子，细胞因子，细胞存活因子，血管生成和活性氧的生长因子的基因的转录，这些基因被认为会影响癌症病理病理病理病理病理病理病理病理病理病理病理病理病理病理病理病理病理病理病理病理病理病理。。 TNF和IL-1通过结合其受体来启动细胞信号传导，并导致激活两个主要的转录因子NF-KB和AP1，它们介导了大多数转录激活。在过去的十年中，信号传导机制邻近受体或转录因子一直是广泛的研究。但是，我们对受体复合物和转录因子之间的信号传导中间体的理解仍然不完整。在这个项目中，我们已经确定TAK1 MAPKKK是TNF/IL-1信号传导途径的重要中间体，将受体与下游效应子联系起来。在细胞的TNF和IL-1处理后，TAK1被激活，然后刺激MAPK Cascade和IKB激酶途径，这些途径分别激活了最终激活API和NF-KB。我们还将TAB2和TAB3隔离为TAK1结合伙伴，并证明TAB2和TAB3作为链接TAK1与受体复合物的适配器的功能。 TAB2和TAB3对于TNF/IL-1激活的TAK1必不可少。这些发现为抑制炎症反应以及慢性炎症性疾病的肿瘤进展提供了潜在的新治疗靶标。