Inclusion body myositis: expression of extracellular signal-regulated kinase and its substrate.
OBJECTIVE
To assess abnormal intracellular signal transduction in inclusion body myositis (IBM).


BACKGROUND
Mitogen-activated protein kinases (MAPKs) play pivotal roles in intracellular signal transduction and regulate cell growth and differentiation. Upon their activation, MAPKs translocate from the cytoplasm into the nucleus.


METHODS
The authors investigated the localization of several forms of the MAPK family-extracellular signal-regulated kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 MAPK (p38)-in 10 patients with sporadic IBM and in 52 control subjects. The relationship between the localization of immunopositive deposits and nuclei was tested with bis-benzimide.


RESULTS
Vacuolated fibers in IBM displayed very strong focal immunoreactivity of ERK, but not of JNK or p38. The ERK-positive deposits in these vacuolated fibers colocalized with the nuclear substrate of ERK, Elk-1. ERK- and Elk-1-positive deposits were located frequently on the surface of the nuclei in vacuolated fibers in IBM. Similar findings to those of sporadic IBM were observed in three patients with distal myopathy with rimmed vacuoles, but not in eight normal or the other 41 disease controls.


CONCLUSIONS
There is evidence for impaired molecular transport to the nucleus from the cytoplasm in the vacuolated fibers in IBM. This could be due to cytoplasmic aggregation of ERK and Elk-1 or to abnormal nuclear pore machinery involved in the transport of ERK and its substrate upon ERK activation.
Nakano
S
S
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. snakano@isola.kuhp.kyoto-u.ac.jp
Shinde
A
A
Kawashima
S
S
Nakamura
S
S
Akiguchi
I
I
Kimura
J
J
D000328:Adult; D000368:Aged; D000906:Antibodies; D002467:Cell Nucleus / Q000201:enzymology; D004268:DNA-Binding Proteins; D005110:Extracellular Space / Q000201:enzymology; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000032:analysis; D013379:Substrate Specificity; D014157:Transcription Factors; D014617:Vacuoles / Q000737:chemistry / Q000473:pathology; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases
D000906:Antibodies; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases