| Project/Area Number |
12219207
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
|
| Allocation Type | Single-year Grants |
|---|
| Review Section |
Biological Sciences
|
|---|
| Research Institution | Nagoya University |
|---|
Principal Investigator |
MATSUMOTO Kunihiro Nagoya University, Graduate School, Professor, 大学院理学研究科, 教授 (70116375)
|
|---|
| Project Period (FY) |
2000 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| Budget Amount *help |
¥218,300,000 (Direct Cost: ¥218,300,000)
Fiscal Year 2004: ¥44,000,000 (Direct Cost: ¥44,000,000)
Fiscal Year 2003: ¥49,500,000 (Direct Cost: ¥49,500,000)
Fiscal Year 2002: ¥45,000,000 (Direct Cost: ¥45,000,000)
Fiscal Year 2001: ¥42,600,000 (Direct Cost: ¥42,600,000)
Fiscal Year 2000: ¥37,200,000 (Direct Cost: ¥37,200,000)
|
|---|
| Keywords | signal transduction / cancer / activation of NF-κB / TAK1 / MAP kinase / TNF / IL-1 / EBウイルス / LMP1 / TRAF6 / TAB2 / シグナル伝達経路 / 炎症作用 / 遺伝子 / 発現制御 / 発生・分化 / シグナル電動 / 生体分子 / MAP Kinase |
|---|
| Research Abstract |
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.
|
