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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging
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Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging

机译：突变型层粘蛋白A导致人类衰老导致的有丝分裂和细胞周期进程的变化

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摘要

Mutations in the gene encoding nuclear lamin A (LA) cause the premature aging disease Hutchinson-Gilford Progeria Syndrome. The most common of these mutations results in the expression of a mutant LA, with a 50-aa deletion within its C terminus. In this study, we demonstrate that this deletion leads to a stable farne-sylation and carboxymethylation of the mutant LA (LAΔ50/prog-erin). These modifications cause an abnormal association of LAΔ50/ progerin with membranes during mitosis, which delays the onset and progression of cytokinesis. Furthermore, we demonstrate that the targeting of nuclear envelope/lamina components into daughter cell nuclei in early G_1 is impaired in cells expressing LAΔ50/ progerin. The mutant LA also appears to be responsible for defects in the retinoblastoma protein-mediated transition into S-phase, most likely by inhibiting the hyperphosphorylation of retinoblastoma protein by cyclin D1/cdk4. These results provide insights into the mechanisms responsible for premature aging and also shed light on the role of lamins in the normal process of human aging.
机译：编码核纤层蛋白A（LA）的基因中的突变会导致过早衰老的Hutchinson-Gilford早衰综合症。这些突变中最常见的导致突变型LA的表达，其C端缺失50个氨基酸。在这项研究中，我们证明了这种缺失导致突变型LA（LAΔ50/ prog-erin）的稳定的法呢基化和羧甲基化。这些修饰会导致有丝分裂期间LAΔ50/ progerin与膜的异常缔合，从而延迟胞质分裂的发生和发展。此外，我们证明，在表达LAΔ50/ progerin的细胞中，早期G_1的核被膜/椎板成分进入子细胞核的靶向性受损。突变体LA似乎也负责视网膜母细胞瘤蛋白介导的向S期的转变，最有可能是通过抑制细胞周期蛋白D1 / cdk4引起的视网膜母细胞瘤蛋白的过度磷酸化。这些结果为导致过早衰老的机制提供了见识，并阐明了lamins在人类正常衰老过程中的作用。

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