Role of the NO-activated MAP kinase pathways in carcinogenesis

NO 激活的 MAP 激酶途径在癌发生中的作用

• 批准号: 13470400
• 负责人: TAKEDA Kohsuke
• 金额: $ 8.77万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470400/
• 关键词: Nitric oxide(NO); Signal transduction; MAP kinase; Apoptosis; stress

In this research project, we have shown the following two results.1. We have shown that nitric oxide (NO) strongly activated apoptosis signal-regulating kinase 1(ASK1), which is known to regulate the JNK and p38 MAP kinase pathways, and that NO-induced early activation of p38 was impaired in mouse embryonic fibroblasts obtained from ASK 1-deficient mice. These results strongly suggest that ASK1 is a pivotal regulator of NO-induced activation of the MAP kinase pathways.2. Recently, we have found that calcium influx activates ASK1. It has been reported that the calcium influx triggers the NO production and that, conversely, NO regulates the calcium homeostasis, suggesting the intimate relationship between NO and calcium signaling. To know how calcium signal affects NO-medicated activation of the ASK1-MAP kinase pathways in calcium signaling, we investigated the activation mechanism of ASK1 by calcium signal. We have shown that a kinase cascade composed of calcium/calmodulin-dependent protein kinase type II (CaMKII)-ASK1-MKK3/MKK6-p38 constituted a novel calcium-signaling pathway. Calcium influx activated CaMKII, and activated CaMKII recruited and activated ASK1 by phosphorylation. Moreover, calcium influx evoked by membrane depolarization in primary neurons and synaptosomes induced strong activation of p38, which was impaired in those derived from ASK 1-deficient mice. Thus, ASK1 appears to be a critical intermediate of calcium signaling between CaMKII and p38.

在本研究项目中，我们得到了以下两个结果：1.我们已经证明，一氧化氮（NO）强烈激活细胞凋亡信号调节激酶1（ASK 1），已知该激酶可调节JNK和p38 MAP激酶途径，并且NO诱导的p38早期激活在来自小鼠的胚胎成纤维细胞中受损1-缺陷小鼠。这些结果强烈表明ASK 1是NO诱导的MAP激酶通路激活的关键调节因子.最近，我们发现钙内流激活ASK 1。已有研究表明，钙离子内流触发了NO的产生，相反，NO调节钙稳态，表明NO与钙信号传导之间存在密切关系。为了了解钙信号如何影响NO介导的钙信号转导中的ASK 1-MAP激酶通路的激活，我们研究了钙信号对ASK 1的激活机制。我们已经证明，由钙/钙调蛋白依赖性蛋白激酶II（CaMKII）-ASK 1-MKK 3/MKK 6-p38组成的激酶级联构成了一种新的钙信号通路。钙内流激活CaMKII，激活CaMKII募集并通过磷酸化激活ASK 1。此外，在初级神经元和突触体中由膜去极化引起的钙内流诱导p38的强烈激活，这在来自ASK 1缺陷小鼠的那些中受损。因此，ASK 1似乎是CaMKII和p38之间钙信号传导的关键中间体。

项目成果

Nishitoh, H., et al.: "ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats."Genes & Dev.. 16. 1345-1355 (2002)

Nishitoh, H. 等人：“ASK1 对于由扩展的多聚谷氨酰胺重复序列引发的内质网应激诱导的神经元细胞死亡至关重要。”

Sawada, Y., et al.,: "Rapl is involved in cell stretching modulation of p38 but not ERK or JNK MAP kinase"J.Cell Sci.. 114. 1221-1227 (2001)

Sawada, Y., et al.，：“Rapl 参与 p38 的细胞拉伸调节，但不参与 ERK 或 JNK MAP 激酶”J.Cell Sci.. 114. 1221-1227 (2001)

Inoshita, S. etal.,: "Phosphorylation and Inactivation of Mcl-1 by c-Jun N-terminal Kinase (JNK) in response to oxidative stress"J. Biol. Chem.,. 277. 43730-43734 (2002)

Inoshita, S. 等人：“c-Jun N 末端激酶 (JNK) 响应氧化应激导致 Mcl-1 磷酸化和失活”J.

Matsuzawa, A. et al.: "Physiological roles of ASK1-mediated signal transduction in oxidative stress-and endoplasmic reticulum stress-induced apoptosis : advanced findings from ASK1 knockout mice"Antioxid. Redox Signal. 4. 415-425 (2002)

Matsuzawa, A. 等人：“ASK1 介导的信号转导在氧化应激和内质网应激诱导的细胞凋亡中的生理作用：来自 ASK1 敲除小鼠的最新发现”抗氧化。

Matsuzawa, A. et al.: "Physiological roles of ASK1-mediated signal transduction in oxidative stress-and endoplasmic reticulum stress-induced apoptosis : advanced findings from ASK1 knockout mice"Antioxidants and Redox Signal. (in press). (2002)

Matsuzawa, A. 等人：“ASK1 介导的信号转导在氧化应激和内质网应激诱导的细胞凋亡中的生理作用：ASK1 敲除小鼠的最新发现”抗氧化剂和氧化还原信号。