Analysis of the Roles for Stress-activated MAP kinases in Oral Muco-epithelium

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This study aimed at analyzing the roles for stress-activated MAP kinases in the muco-epithelial tissues with special focus on the roles of Apoptosis Signal-regulating Kinase 1(ASK1) and ASK2. Physiological and Patho-physiological functions of ASK1 were analyzed by generation of ASK1 knock-out mouse, and following findings were obtained.1) By deleting ASK1 in mice, TNF- and H_2O_2-induced sustained activations of JNK and p38 were found to be lost in ASK1-/- embryonic fibroblasts, and ASK1-/- cells were resistant to TNF- and H_2O_2-induced apoptosis. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis.2) Homo-oligomerization-dependent auto-phosphorylation was found to be an important step for activation of ASK1.3) ASK1 induces not only apoptosis but also differentiation of keratinocytes depending on its extent of activation.4) At least two phosphatases PP5 and CDC25A were found to inhibit ASK1 activity through different mechanisms.5) Endoplasmic reticulum (ER) stress was found to induce apoptosis through ASK1-MAP kinase cascades.