title: Long-term expression of the lamin A mutant associated with dilated cardiomyopathy induces senescence.
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.
authors.affiliation: Graduate School of Life Science, University of Hyogo, Koto, Kamigori, Hyogo, 678-1297, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Moriuchi
authors.forename: Takuya
authors.initials: T
authors.lastname: Muraoka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mio
authors.forename: Takashi
authors.initials: T
authors.lastname: Osumi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Hirose
mesh_terms: D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D015726:Giant Cells / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006367:HeLa Cells; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D034921:Lamin Type B / Q000378:metabolism; D050356:Lipid Metabolism; D009154:Mutation; D058207:Sumoylation
chemical_list: D006570:Heterochromatin; D034904:Lamin Type A; D034921:Lamin Type B