Mir-23a induces telomere dysfunction and cellular senescence by inhibiting TRF2 expression.
Mir-23a induces telomere dysfunction and cellular senescence by inhibiting TRF2 expression.
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Mir-23a 通过抑制 TRF2 表达诱导端粒功能障碍和细胞衰老
DOI：
10.1111/acel.12304
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发表时间：
2015-06
期刊：
影响因子：
7.8
通讯作者：
Songyang Z
中科院分区：
文献类型：
--
作者：
Luo Z;Feng X;Wang H;Xu W;Zhao Y;Ma W;Jiang S;Liu D;Huang J;Songyang Z
端粒重复序列结合因子2（TRF 2）是端粒维持所必需的，并与DNA损伤反应和衰老有关。TRF 2抑制诱导的端粒功能障碍可加速人成纤维细胞的细胞衰老。虽然先前的工作已经证明了多种因素可以转录和转录后调节TRF 2表达，但microRNA（miRNAs）是否也参与转录后调节TRF 2水平仍然是未知的。为了更好地了解控制TRF 2的调控途径，我们使用miRNA表达文库进行了大规模的荧光素酶报告基因筛选，并鉴定了四种可以靶向人类TRF 2并显著降低内源性TRF 2蛋白水平的miRNA。特别是，我们的数据显示，miR-23 a可以直接靶向TRF 2的3′非翻译区（3′UTR）。miR-23 a的过表达不仅减少了端粒结合的TRF 2和增加了端粒功能障碍诱导的病灶（TIF），而且加速了人成纤维细胞的衰老，这可以通过异位表达的TRF 2来挽救。我们的研究结果表明，TRF 2是miR-23 a的特异性靶点，并揭示了miR-23 a在端粒调控和细胞衰老中以前未知的作用。
Telomeric repeat binding factor 2 (TRF2) is essential for telomere maintenance and has been implicated in DNA damage response and aging. Telomere dysfunction induced by TRF2 inhibition can accelerate cellular senescence in human fibroblasts. While previous work has demonstrated that a variety of factors can regulate TRF2 expression transcriptionally and post-translationally, whether microRNAs (miRNAs) also participate in post-transcriptionally modulating TRF2 levels remains largely unknown. To better understand the regulatory pathways that control TRF2, we carried out a large-scale luciferase reporter screen using a miRNA expression library and identified four miRNAs that could target human TRF2 and significantly reduce the level of endogenous TRF2 proteins. In particular, our data revealed that miR-23a could directly target the 3′ untranslated region (3′UTR) of TRF2. Overexpression of miR-23a not only reduced telomere-bound TRF2 and increased telomere dysfunction-induced foci (TIFs), but also accelerated senescence of human fibroblast cells, which could be rescued by ectopically expressed TRF2. Our findings demonstrate that TRF2 is a specific target of miR-23a, and uncover a previously unknown role for miR-23a in telomere regulation and cellular senescence.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
21.3
作者：
Fujita, Kaori;Horikawa, Izumi;Mondal, Abdul M.;Jenkins, Lisa M. Miller;Appella, Ettore;Vojtesek, Borivoj;Bourdon, Jean-Christophe;Lane, David P.;Harris, Curtis C.
通讯作者：
Harris, Curtis C.
影响因子：
7.8
作者：
Martínez P;Ferrara-Romeo I;Flores JM;Blasco MA
通讯作者：
Blasco MA
miR-23a-27a-24-2簇的上调诱导人类胚胎肾细胞中的caspase依赖性和非依赖性凋亡。
影响因子：
3.7
作者：
Chhabra R;Adlakha YK;Hariharan M;Scaria V;Saini N
通讯作者：
Saini N