Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Proc Jpn Acad Ser B Phys Biol Sci. 2012;88(8):434-53. doi: 10.2183/pjab.88.434.
Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family that activates downstream MAP kinases (MAPKs), c-Jun N-terminal kinases (JNKs) and p38 MAPKs, in response to various stresses, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, lipopolysaccharide, and calcium overload. Activation of the JNK and p38 pathways induces stress responses such as cell death, differentiation, and the production of inflammatory cytokines. A series of studies using ASK1-deficient mice have indicated that ASK1 plays important roles in many stress-related diseases, including cardiovascular and neurodegenerative diseases, suggesting that small compounds that inhibit ASK1 activity could possibly be used for the amelioration of the development and/or progression of these diseases. In this review, we provide an overview of the pathophysiological roles of ASK1-dependent signaling pathways and discuss the mechanistic basis for how these could serve as potential therapeutic targets.
凋亡信号调节激酶 1（ASK1）是丝裂原活化蛋白激酶激酶激酶（MAP3K）家族的一员，可响应各种应激源（如活性氧（ROS）、内质网（ER）应激、脂多糖和钙超载）激活下游的 MAP 激酶（MAPKs）、c-Jun N 末端激酶（JNKs）和 p38 MAPKs。JNK 和 p38 通路的激活诱导应激反应，如细胞死亡、分化和炎症细胞因子的产生。一系列使用 ASK1 缺陷型小鼠的研究表明，ASK1 在许多与应激相关的疾病中发挥重要作用，包括心血管疾病和神经退行性疾病，这表明抑制 ASK1 活性的小分子可能可用于改善这些疾病的发生和/或进展。在这篇综述中，我们概述了 ASK1 依赖性信号通路的病理生理作用，并讨论了这些信号通路作为潜在治疗靶点的机制基础。
