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

慢性炎症是许多人类癌症发展的原因。促炎细胞因子，肿瘤坏死因子和白介素1，激活编码趋化因子、细胞因子、细胞生存因子、参与血管生成的生长因子和活性氧的基因的转录，这些被认为影响癌症的病理。肿瘤坏死因子和白介素1通过与其受体结合来启动细胞信号转导，并导致两个主要的转录因子-核因子-kB和AP1的激活，它们介导了大部分的转录激活。在过去的十年里，受体或转录因子近端的信号机制已经被广泛研究。然而，我们对受体复合体和转录因子之间的信号中间产物的了解仍然不完整。在这个项目中，我们已经确定了TAK1 MAPKKK是连接受体和下游效应器的TNF/IL-1信号通路的重要中间体。在肿瘤坏死因子和白介素1作用于细胞后，TAK1被激活，然后刺激MAPK级联通路和IKB激酶通路，最终分别激活API和NF-kB。我们还分离了Tab2和Tab3作为TAK1的结合伙伴，并证明了Tab2和Tab3是连接TAK1与受体复合体的接头。Tab2和Tab3是由肿瘤坏死因子/白介素1激活的TAK1所必需的。这些发现为抑制慢性炎症性疾病的炎症反应和肿瘤进展提供了潜在的新的治疗靶点。

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.