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)