| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
In this research project, we have shown the following three results.
1) Apoptosis Signal-regulating Kinase (ASK) 1 is activated in response to various cytotoxic stresses including TNF, Fas and reactive oxygen species (ROS) such as H2O2 and activates c-Jun NH2-terminal Kinase (JNK) and p38. We have shown by deleting ASK1 in mice that TNF- and H2O2-induced sustained activations of JNK and p38 are lost in ASK1-/- embryonic fibroblasts, and that ASK1-/- cells are resistant to TNF- and H2O2-induced apoptosis. TNF-induced apoptosis requires ROS-dependent activation of ASK1-JNK/p38 pathways. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis. (EMBO Reports, Vol. 2, p222-228 2001)
2) A yeast two-hybrid screening identified a serine/threonine protein phosphatase 5 (PP5) as a binding partner of ASK1. PP5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ASK1 and thereby inactivated ASK1
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activity in vitro and in vivo. The interaction between PP5 and ASK1 was induced by H2O2 treatment and was followed by the decrease in ASK1 activity. PP5 inhibited not only H2O2-induced sustained activation of ASK1 but also ASK1-dependent apoptosis. Thus, PP5 appears to act as a physiological inhibitor of ASK1-JNK/p38 pathways by negative feedback. (EMBO Journal, Vol. 20, p6028-6036, 2001)
3) Accumulation of misfolded proteins within the ER lumen induces cellular stress and cell death, and ER stress has been implicated in human neurodegenerative disorders. However, the molecular mechanism of ER stress-induced cell death was controversial. We have shown the role of ASK1 in the ER stress signaling. Activated IRE1, ER-resident type I transmembrane serine/threonine protein kinase, recruits TRAF2 and ASK1. In untransfected cells, ASK1 is activated by the ER stressors. By using ASK1-/-cells, ASK1 was shown to be required for the ER stress-induced JNK activation and apoptosis. These results indicate that IRE1-TRAF2-ASK1 axis is essential for the ER stress-induced JNK activation and apoptosis. Furthermore, we have shown the evidence that this ER stress-induced cell death pathway plays a central role in the pathogenesis of neurodegenerative disorders. (Genes & Development Vol. 16, p1345-1355, 2002) Thus, ER stress-mediated ASK1 pathway may be one of the therapuitic targets for diseases. Less
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