Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging
Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging
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DOI：
10.1073/pnas.0700854104
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发表时间：
2007-03-20
影响因子：
11.1
通讯作者：
Goldman, Robert D.
中科院分区：
文献类型：
--
作者：
Dechat, Thomas;Shimi, Takeshi;Goldman, Robert D.
编码核纤层蛋白 A (LA) 的基因突变会导致早衰疾病哈钦森-吉尔福德早衰综合症。这些突变中最常见的结果是表达突变型 LA，其 C 末端有 50 个氨基酸缺失。在这项研究中，我们证明这种缺失导致突变体 LA (LA Delta 50/progerin) 的稳定法尼基化和羧甲基化。这些修饰导致 LA Delta 50/progerin 在有丝分裂期间与细胞膜异常关联，从而延迟了胞质分裂的发生和进展。此外，我们证明，在表达 LA Delta 50/progerin 的细胞中，核膜/核纤层成分在早期 G 期靶向子细胞核的能力受到损害。突变的 LA 似乎还导致视网膜母细胞瘤蛋白介导的 S 期转变缺陷，最有可能是通过细胞周期蛋白 D1/cdk4 抑制视网膜母细胞瘤蛋白的过度磷酸化。这些结果提供了对过早衰老机制的见解，并揭示了核纤层蛋白在人类正常衰老过程中的作用。
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 farnesylation and carboxymethylation of the mutant LA (LA Delta 50/progerin). These modifications cause an abnormal association of LA Delta 50/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, is impaired in cells expressing LA Delta 50/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.