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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发展的原因。促炎性细胞因子肿瘤坏死因子（TNF）和白细胞介素1（IL-1）激活编码趋化因子、细胞因子、细胞存活因子、参与血管生成的生长因子和活性氧的基因的转录，其被认为影响癌症病理学。TNF和IL-1通过与其受体结合启动细胞信号传导，并导致激活两个主要的转录因子NF-κ B和AP 1，它们介导大部分的转录激活。近十年来，无论是受体还是转录因子的信号转导机制都得到了广泛的研究。然而，我们对受体复合物和转录因子之间的信号中间体的理解仍然不完整。在本项目中，我们已经确定TAK 1 MAPKKK是TNF/IL-1信号通路中连接受体和下游效应物的重要中间体。TAK 1在TNF和IL-1处理细胞后被激活，然后刺激MAPK级联和IkB激酶途径，其最终分别激活API和NF-kB。我们还分离了TAB 2和TAB 3作为TAK 1结合伴侣，并证明TAB 2和TAB 3作为衔接子将TAK 1连接到受体复合物。TAB 2和TAB 3是TNF/IL-1激活TAK 1所必需的。这些发现提供了潜在的新的治疗靶点，以抑制炎症反应以及慢性炎症性疾病中的肿瘤进展。