Analysis of MAP kinase cascades in inclusion body myositis

包涵体肌炎中 MAP 激酶级联反应的分析

• 批准号: 13670676
• 负责人: NAKANO Satoshi
• 金额: $ 2.5万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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/grant/KAKENHI-PROJECT-13670676/
• 关键词: inclusion body myositis; MAP kinase; ERK; MAP kinase phosphatase; MAP kinase Kinase; phosphorylation; nuclear transport; importin

Inclusion body myositis(IBM) is suggested to be the most common muscle disease among the elderly and refractory to various therapies including corticosteroids and immuno-suppressants. In some muscle fibers in biopsied muscles in IBM, there are inclusions that are abnormally phosphorylated. Based on this observation, we started to investigate the abnormality of phosporylation and dephosphorylation in IBM.n this project, we have demonstrated perinuclear accumulation of extracellular signal-regulated protein kinase(ERK) that belongs to the MAP kinase family and its nuclear substrate, Elk-1 in abnormal fibers in IBM. We then tested activators and inactivators of MAP kinases in IBM. MAP kinase kinases that activate MAP kinases were not up-regulated in IBM. Among MAP kinase phosphatases that inactivate MAP kinase, MAP kinase phosphatase-1 was induced in abnormal fibers. The up-regulation of this phosphatase may probably be to down-regulate ERK.These results suggest that perinuclear accumulation of ERK protein is due to impairment of nuclear translocation of ERK that is activated in physiological levels. We are currently investigating nuclear transport factors in IBM.

包涵体肌炎（IBM）被认为是老年人最常见的肌肉疾病，包括皮质类固醇和免疫抑制剂在内的各种治疗都难以治愈。在IBM活检肌肉的一些肌纤维中，有异常磷酸化的内含物。基于这一观察，我们开始研究IBM中磷酸化和去磷酸化的异常。在这个项目中，我们在IBM的异常纤维中发现了属于MAP激酶家族的细胞外信号调节蛋白激酶（ERK）及其核底物Elk-1的核周积累。然后，我们在IBM中测试了MAP激酶的激活剂和失活剂。激活MAP激酶的MAP激酶在IBM中没有上调。在灭活MAP激酶的MAP激酶磷酸酶中，MAP激酶磷酸酶-1在异常纤维中被诱导。这种磷酸酶的上调可能是为了下调ERK。这些结果表明，ERK蛋白的核周积累是由于ERK在生理水平上激活的核易位受损。我们目前正在IBM研究核传输因子。

项目成果

Nakamoto, M., Nakano, S., Kawashima, S., Ihara, M., Nishimura, Y., Shinde, A., Kakizuka, A.: "Unequal crossing-over in unique PABP2 mutations in Japanese patients-a possible cause of oculopharyngeal muscular dystrophy."Arch.Neurol.. 59. 474-477 (2002)

Nakamoto, M.、Nakano, S.、Kawashima, S.、Ihara, M.、Nishimura, Y.、Shinde, A.、Kakizuka, A.：“日本患者中独特的 PABP2 突变的不平等交叉——可能

Nakano, S., Shinde, A., Kawashima, S., Nakamura, S., Akiguchi, I., Kimura, J.: "Inclusion body myositis : expression of extracellular signal-regulated kinase and its substrate."Neurology. 56. 87-93 (2001)

Nakano, S.、Shinde, A.、Kawashima, S.、Nakamura, S.、Akiguchi, I.、Kimura, J.：“包涵体肌炎：细胞外信号调节激酶及其底物的表达。”神经病学。

八木彩香 他: "下垂足、下垂手で再燃した重症筋無力症の1例"神経内科. 58. 189-192 (2003)

Ayaka Yagi 等人：“伴有足下垂和手下垂的复发性重症肌无力病例”《神经病学》58. 189-192 (2003)。

Shinichi Nakamura: "Immunohistochemical localization of phosphoinositide 3-kinase in brains with multiple system atrophy"Clin Neuropathol. 20. 243-247 (2001)

Shinichi Nakamura：“多系统萎缩大脑中磷酸肌醇 3-激酶的免疫组织化学定位”Clin Neuropathol。

Mika Nakamoto, et al.: "Unique PABP2 mutations in Japanese patients suggest oculopharyngeal muscular dystrophy is caused by unequal crossing over.."Arch Neurol. 59. 474-477 (2002)

Mika Nakamoto 等人：“日本患者中独特的 PABP2 突变表明眼咽肌营养不良症是由不平等交叉引起的。”Arch Neurol。