Analysis of MAP kinase cascades in inclusion body myositis

包涵体肌炎(IBM)被认为是老年人最常见的肌肉疾病，对包括皮质类固醇和免疫抑制剂在内的各种治疗方法都是无效的。在IBM活体肌肉中的一些肌肉纤维中，存在异常磷酸化的包裹体。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在IBM异常纤维中的核周积聚。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。在使MAP激酶失活的MAPK磷酸酶中，MAPK磷酸酶-1在异常纤维中被诱导。这种磷酸酶的上调可能是ERK的下调。这些结果表明，ERK蛋白在核周的积聚是由于在生理水平激活的ERK的核转位受损所致。我们目前正在调查IBM的核运输因素。

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.