Molecular mechanisms of response of living body to environmental stress

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1.We investigated the role(s) of PP2Cε in the regulation of IL-1 signaling pathways. Ectopic expression of PP2Cε inhibited the IL-1-and TAK1-induced activation of mitogen-activated protein kinase kinase 4 (MKK4)-c-Jun N-terminal kinase or MKK3-p38 signaling pathway. PP2Cε dephosphorylated TAK1 in vitro. Co-immunoprecipitation experiments indicated that PP2Cε associates stably with TAK1 and attenuates the binding of TAK1 to MKK4 or MKK6. Ectopic expression of a phosphatase-negative mutant of PP2Cε, PP2Cε (D/A), which acted as a dominant negative form, enhanced both the association between TAK1 and MKK4 or MKK6 and the TAK1-induced activation of an AP-1 reporter gene. The association between PP2Cε and TAK1 was transiently suppressed by IL-1 treatment of the cells. Taken together, these results suggest that, in the absence of IL-1-induced signal, PP2Cε contributes to keeping the TAK1 signaling pathway in an inactive state by associating with and dephosphorylating TAK1.2.We investigated th … More e physiologic functions of PP2Cβ using a gene knockout technique in mice. We found that most PP2Cβ^<Δ/Δ> embryos die between the two-and eight-cell stages, whereas PP2Cβ^<Δ/Δ> ES cells are viable, suggesting that relatively high PP2Cβ expression is required for the early stages of pre-implantation development. PP2Cβ knockdown studies using ES cells revealed that serum-induced activation of p38, but not JNK, ERK, or Akt, was enhanced further by decreased PP2Cβ expression. Since p38 has been implicated in the negative regulation of mitosis in early pre-implantation embryos, these observations raise the possibility that cell division at early cleavage stages might be severely disturbed due to the enhanced activity of p38 in PP2Cβ^<Δ/Δ> embryos.3.We have shown that BMPRII, a BMP type II receptor, associates with JNK through its unique carboxyl-terminal region, which contains a putative JNK binding domain. BMPRII was also able to bind to MKK4, MKK7 and ASK1. BMP2 treatment of cells induced the recruitment of JNK to BMPRII and activated the ASK1 signaling module associated with BMPRII. These results suggest that BMPRII participates in the spatial regulation of the ASK1-JNK signaling pathway as a cell-membrane associated scaffolding protein. Less