Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction.
Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction.
复制标题
核纤层蛋白 A/C 缺乏会导致核力学和机械传导缺陷。
DOI：
10.1172/jci19670
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Lee,RichardT
中科院分区：
文献类型：
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作者：
Lammerding,Jan;Schulze,PChristian;Takahashi,Tomosaburo;Kozlov,Serguei;Sullivan,Teresa;Kamm,RogerD;Stewart,ColinL;Lee,RichardT
LMNA基因突变可导致多种人类疾病，包括Emery-Dreifuss肌营养不良症、扩张型心肌病和Hutchinson-Gilford早衰症。Lamin突变的组织特异性效应尚不清楚，部分原因是Lamin A/C的功能尚未完全确定，但许多肌肉特异性表型表明，Lamin A/C缺陷可能会增加细胞的机械敏感性。为了研究层蛋白A/C在机械转导中的作用，我们将层蛋白A/C缺陷的小鼠胚胎成纤维细胞置于机械应变中，并测量了核机械性能和应变诱导的信号转导。我们发现，在机械应变下，LmNA-/-细胞的核变形增加，机械转导缺陷，生存能力下降。在LmNA-/-细胞中，尽管转录因子结合增加，但在机械刺激或细胞因子刺激下，NF-κB调节的转录被减弱。因此，Lamin A/C缺乏症既与核机制缺陷有关，也与机械激活基因转录受损有关。这些发现表明，在椎板病变中观察到的层蛋白A/C突变的组织特异性效应可能源于不同程度的核机械和转录激活受损。
Mutations in thelamin A/Cgene (LMNA) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. The tissue-specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined, but the many muscle-specific phenotypes suggest that defective lamin A/C could increase cellular mechanical sensitivity. To investigate the role of lamin A/C in mechanotransduction, we subjected lamin A/C–deficient mouse embryo fibroblasts to mechanical strain and measured nuclear mechanical properties and strain-induced signaling. We found thatLmna–/–cells have increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain. NF-κB–regulated transcription in response to mechanical or cytokine stimulation was attenuated inLmna–/–cells despite increased transcription factor binding. Lamin A/C deficiency is thus associated with both defective nuclear mechanics and impaired mechanically activated gene transcription. These findings suggest that the tissue-specific effects of lamin A/C mutations observed in the laminopathies may arise from varying degrees of impaired nuclear mechanics and transcriptional activation.