Progerin impairs vascular smooth muscle cell growth via the DNA damage response pathway.
Progerin impairs vascular smooth muscle cell growth via the DNA damage response pathway.
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DOI：
10.18632/oncotarget.15973
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发表时间：
2017-05-23
期刊：
影响因子：
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通讯作者：
Minamino T
中科院分区：
文献类型：
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作者：
Kinoshita D;Nagasawa A;Shimizu I;Ito TK;Yoshida Y;Tsuchida M;Iwama A;Hayano T;Minamino T
Lamin A基因突变导致多种早衰综合征，包括Hutchinson-Gilford早衰症(HGPS)和非典型Werner综合征。在HGPS(但不是非典型的Werner综合征)中，血管平滑肌细胞的广泛丢失导致心肌梗死并过早死亡。单个基因突变如何导致各种表型的潜在机制在很大程度上尚不清楚。我们使用与孕期综合征有关的层蛋白A的突变形式进行了交互作用组分析。我们发现，负责HGPS的突变体lamin A，即孕激素，不能与DNA损伤反应相关的蛋白质结合，包括DNA依赖的蛋白激酶(DNA-PK)。相反，导致非典型Werner综合征的野生型lamin A和lamin A突变体能够与这些分子结合。我们还发现，在血管平滑肌细胞中强制表达孕激素会导致DNA-PK的激活和细胞生长停滞，而DNA-PK的敲除则会减弱这一作用。P53的缺失也改善了由于孕激素强制表达而对细胞生长的抑制。这些发现提示孕激素激活了DNA损伤反应通路，该通路的失调可能是HGPS患者心血管病理发展的原因。
Mutations of the lamin A gene cause various premature aging syndromes, including Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner syndrome. In HGPS (but not atypical Werner syndrome), extensive loss of vascular smooth muscle cells leads to myocardial infarction with premature death. The underlying mechanisms how single gene mutations can cause various phenotypes are largely unknown. We performed an interactome analysis using mutant forms of lamin A involved in progeroid syndromes. We found that the mutant lamin A responsible for HGPS, known as progerin, could not bind to proteins related to the DNA damage response, including DNA-dependent protein kinase (DNA-PK). In contrast, wild-type lamin A and lamin A mutants causing atypical Werner syndrome were able to bind to these molecules. We also found that forced expression of progerin in vascular smooth muscle cells led to activation of DNA-PK and cellular growth arrest, while knockdown of DNA-PK attenuated this. Deletion of p53 also improved the inhibition of cell growth due to forced expression of progerin. These findings suggested that progerin activates the DNA damage response pathway and that dysregulation of this pathway may be responsible for the development of cardiovascular pathology in patients with HGPS.