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

本研究旨在分析应激激活的MAP激酶在粘膜上皮组织中的作用，特别关注凋亡信号调节激酶1（ASK 1）和ASK 2的作用。通过建立ASK 1基因敲除小鼠模型，分析了ASK 1的生理和病理生理功能，结果表明：1）ASK 1基因敲除后，小鼠胚胎成纤维细胞中TNF和H_2O_2诱导的JNK和p38持续激活消失，ASK 1-/-细胞对TNF和H_2O_2诱导的凋亡具有抵抗性。因此，在本发明中，ASK 1是TNF-和氧化应激诱导的JNK/p38持续激活和角质形成细胞凋亡所选择性需要的。2）同源寡聚化依赖的自磷酸化被发现是ASK 1激活的重要步骤。3）ASK 1不仅诱导角质形成细胞凋亡，而且根据其激活程度诱导角质形成细胞分化。4）发现至少两种磷酸酶PP 5和CDC 25 A通过不同的机制抑制ASK 1的活性。5）内质网应激通过ASK 1-MAP激酶级联反应诱导细胞凋亡。

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.