Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts
Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts
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DOI：
10.1172/jci43578
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发表时间：
2011-07-01
影响因子：
15.9
通讯作者：
Collins, Francis S.
中科院分区：
文献类型：
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作者：
Cao, Kan;Blair, Cecilia D.;Collins, Francis S.
Hutchinson-Gilford早老综合征（HGPS）是一种严重的早衰性疾病，由核纤层蛋白A基因（LMNA）的点突变引起。这种突变组成性激活了一个隐蔽的剪接供体位点，产生了一种突变的核纤层蛋白A蛋白，称为早老蛋白。最近的研究表明，早老蛋白在正常的人体细胞和组织中也以低水平产生。然而，正常个体的正常衰老和早老蛋白产生之间的因果关系尚未确定。在这项研究中，我们已经表明，在正常人成纤维细胞，细胞衰老过程中的端粒损伤在激活早老蛋白的生产中起着致病作用。还发现进行性端粒损伤导致多个其他基因中的选择性剪接的广泛变化。有趣的是，在不需要端粒缩短的细胞衰老过程中没有观察到早老蛋白的产生升高。两者合计，我们的研究结果表明，端粒功能障碍和早老蛋白的生产在诱导细胞衰老过程中的协同关系，提供机制的洞察如何早老蛋白可能参与正常的衰老过程。
Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.