RRC ID |
67655
|
著者 |
Moriuchi T, Muraoka T, Mio K, Osumi T, Hirose F.
|
タイトル |
Long-term expression of the lamin A mutant associated with dilated cardiomyopathy induces senescence.
|
ジャーナル |
Genes Cells
|
Abstract |
Mutation of the lamin A gene (LMNA) causes a diverse range of diseases referred to as laminopathies. Because most laminopathies have a dominant inheritance pattern and progress gradually, cultured cells stably expressing mutant lamin A at the same level as endogenous wild-type cells are required for chronological analysis. In this study, we showed that an expression system involving a lentiviral vector that carries the human metallothionein gene basal promoter ensures stable and basal-level expression of proteins and is thus suitable for investigating the properties of lamin A mutants. The small ubiquitin-related modifier (SUMO) modification (SUMOylation)-defective E203G mutant that is associated with familial dilated cardiomyopathy exhibited abnormal subnuclear distribution and inhibited normal localization of WT lamin A in a dominant-negative manner. Low-level and long-term expression of the E203G mutant resulted in multinucleated giant cells, aberrant lipid droplet accumulation in the cytoplasm and premature senescence. Expression of another SUMOylation-defective mutant (K201R) did not induce any phenotypes observed in cells expressing E203G. These results indicate that the E203G mutant may inhibit the normal functions of wild-type lamin A in a dominant-negative manner, but a defect in SUMOylation itself may not be involved in disease pathogenesis.
|
巻・号 |
19(12)
|
ページ |
901-18
|
公開日 |
2014-12-1
|
DOI |
10.1111/gtc.12189
|
PMID |
25319090
|
MeSH |
Cardiomyopathy, Dilated / metabolism
Cardiomyopathy, Dilated / pathology*
Cell Nucleus / metabolism
Cell Proliferation
Cellular Senescence
Giant Cells / metabolism
Giant Cells / pathology
HEK293 Cells
HeLa Cells
Heterochromatin / metabolism
Humans
Lamin Type A / metabolism*
Lamin Type B / metabolism
Lipid Metabolism
Mutation
Sumoylation
|
IF |
1.655
|
リソース情報 |
遺伝子材料 |
pCAG-HIVgp (RDB04394)
pCMV-VSV-G-RSV-Rev (RDB04393) |