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Long‐term expression of the lamin A mutant associated with dilated cardiomyopathy induces senescence
Author(s) -
Moriuchi Takanobu,
Muraoka Takuya,
Mio Kazuhiro,
Osumi Takashi,
Hirose Fumiko
Publication year - 2014
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12189
Subject(s) - biology , lamin , senescence , mutant , dilated cardiomyopathy , microbiology and biotechnology , cardiomyopathy , genetics , medicine , heart failure , gene , nucleus
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 ( SUMO ylation)‐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 SUMO ylation‐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 SUMO ylation itself may not be involved in disease pathogenesis.