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

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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.