Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance.
Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance.
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DOI：
10.1038/ncb1818
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发表时间：
2009-01
影响因子：
21.3
通讯作者：
Lu, Kun Ping
中科院分区：
文献类型：
--
作者：
Lee, Tae Ho;Tun-Kyi, Adrian;Shi, Rong;Lim, Jormay;Soohoo, Christina;Finn, Greg;Balastik, Martin;Pastorino, Lucia;Wulf, Gerburg;Zhou, Xiao Zhen;Lu, Kun Ping
端粒对于维持细胞增殖能力是必不可少的，并且它们的丢失与衰老有关。端粒维持中的关键调节因子是端粒蛋白TRF 1，其也在针对Pin 1的相同筛选中被鉴定为Pin 2。Pin 1是一种独特的脯氨酰异构酶，在磷酸化后调节蛋白质的构象和功能。然而，很少有人知道的作用，Pin 1在端粒调控和TRF 1的上游信号的调制。在这里，我们确定TRF 1作为一个主要的保守底物的Pin 1在端粒的维护和老化。Pin 1抑制使TRF 1对蛋白质降解具有抗性，增强TRF 1与端粒的结合，并导致人类细胞和小鼠中端粒的逐渐丢失。Pin 1缺陷型小鼠在一代内也表现出广泛的过早衰老表型，与连续4-5代后的端粒酶缺陷型小鼠相似。因此，Pin 1是TRF 1稳定性、端粒维持和衰老的重要新调节因子。
Telomeres are essential for maintaining cellular proliferative capacity and their loss has been implicated in aging. A key regulator in telomere maintenance is the telomeric protein TRF1, which was also identified as Pin2 in a same screen for Pin1. Pin1 is a unique prolyl isomerase that regulates protein conformation and function after phosphorylation. However, little is known about the role of Pin1 in telomere regulation and the modulation of TRF1 by upstream signals. Here we identify TRF1 as a major conserved substrate for Pin1 during telomere maintenance and aging. Pin1 inhibition renders TRF1 resistant to protein degradation, enhances TRF1 binding on telomeres, and leads to gradual telomere loss in human cells and in mice. Pin1-deficient mice also display widespread premature aging phenotypes within just one generation similar to those in telomerase-deficient mice after 4–5 consecutive generations. Thus, Pin1 is an essential novel regulator of TRF1 stability, telomere maintenance and aging.
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