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

口腔粘膜上皮中应激激活 MAP 激酶的作用分析

• 批准号: 12470396
• 负责人: ICHIJO Hidenori
• 金额: $ 10.3万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470396/
• 关键词: ASK1; ASK2; MAP kinase; apoptosis; stress; Nef; c-Myc; TAK1

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.

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，特别是凋亡信号调节蛋白1(ASK1)和ASK2的作用。对ASK1基因敲除小鼠的生理和病理生理功能进行了分析，结果表明：1)在ASK1基因敲除小鼠中，肿瘤坏死因子和过氧化氢诱导的JNK和p38的持续激活在ASK1/胚胎成纤维细胞中消失，ASK1-/-细胞对肿瘤坏死因子和过氧化氢诱导的细胞凋亡具有抵抗力。因此，在肿瘤坏死因子和氧化应激诱导的JNK/p38的持续激活和细胞凋亡中，ASK1是选择性必需的。2)同源寡聚依赖的自动磷酸化被发现是激活ASK1的重要步骤。3)ASK1不仅诱导细胞凋亡，而且根据其激活的程度而诱导角质形成细胞分化。4)至少有两种磷酸酶PP5和CDC25A被发现通过不同的机制抑制ASK1的活性。5)内质网(ER)应激被发现通过ASK1-MAP激酶级联途径诱导细胞凋亡。

项目成果

Sayama, K. et al.: "Apoptosis signal regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation"J. Biol. Chem.. 276. 999-1004 (2001)

Sayama, K. 等人：“细胞凋亡信号调节激酶 1 (ASK1) 是角质形成细胞分化的细胞内诱导剂”J.

Cho,S.-G.,: "Glutathione s-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1 (ASK1)."J.Biol.Chem.. (in press). (2001)

Cho,S.-G.，：“谷胱甘肽 s-转移酶 mu 通过抑制细胞凋亡信号调节激酶 1 (ASK1) 来调节应激激活信号。”J.Biol.Chem..（出版中）。

Mochida,Y.: "ASK1 inhibits IL-1-induced NF-kB activity through disruption of TRAF6-TAK1 interaction."J.Biol.Chem.. 275. 32747-32752 (2000)

Mochida, Y.：“ASK1 通过破坏 TRAF6-TAK1 相互作用来抑制 IL-1 诱导的 NF-kB 活性。”J.Biol.Chem.. 275. 32747-32752 (2000)

Geleziunas, R. et al.: "HIV-1 nef inhibits ASK1-dependent death signalingproviding a potential mechanism for protecting the infectde host cell"Nature. 410. 834-838 (2001)

Geleziunas, R. 等人：“HIV-1 nef 抑制 ASK1 依赖性死亡信号传导，提供保护受感染宿主细胞的潜在机制”。

Tobiume, K. et al.: "ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis"EMBO reports. 2. 222-228 (2001)

Tobiume, K. 等人：“ASK1 是 JNK/p38 MAP 激酶持续激活和细胞凋亡所必需的”EMBO 报道。