Reciprocal modulation of long noncoding RNA EMS and p53 regulates tumorigenesis.
Reciprocal modulation of long noncoding RNA EMS and p53 regulates tumorigenesis.
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长非编码RNA EMS和p53的相互调节调节肿瘤发生
DOI：
10.1073/pnas.2111409119
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发表时间：
2022-01-18
影响因子：
11.1
通讯作者：
Mei Y
中科院分区：
文献类型：
--
作者：
Wang C;Yang Y;Wu X;Li J;Liu K;Fang D;Li B;Shan G;Mei X;Wang F;Mei Y
作为一种主要的转录因子，抑癌基因p53通过调节靶基因的表达来调节多种细胞过程。尽管众所周知p53是一种转录激活因子，但它也能够抑制许多蛋白质编码基因的表达。然而，它仍然在很大程度上是未知的，是否长的非编码RNA（lncRNA）基因阻遏参与p53功能的调节。在这里，我们表明，p53可以转录抑制lncRNA E2 F1信使RNA（mRNA）稳定因子（EMS）的表达，反之亦然，EMS可以抑制p53的翻译和负调节p53的功能。我们的研究揭示了一个重要的双负反馈回路，控制p53活性，并提供了EMS促进肿瘤发生的机制的见解。p53在肿瘤抑制中起核心作用。越来越多的证据表明，长链非编码RNA（lncRNA）是一类重要的调控分子，控制p53信号。在这里，我们报告说，致癌lncRNA E2 F1信使RNA（mRNA）稳定因子（EMS）和p53相互抑制对方的表达。EMS受p53负调控。作为p53的直接转录抑制靶标，EMS令人惊讶地显示出抑制p53表达。EMS与细胞质多聚腺苷酸化元件结合蛋白2（CPEB 2）相关，因此破坏了CPEB 2-p53 mRNA的相互作用。这种解离减弱了CPEB 2介导的p53 mRNA多聚腺苷酸化并抑制p53翻译。在功能上，EMS能够通过CPEB 2-p53轴至少部分地发挥其致癌活性。总之，这些发现揭示了p53和EMS之间的双重负反馈回路，通过该回路，p53被精细地控制。我们的研究还证明了EMS通过p53的负调节在促进肿瘤发生中的关键作用。
As a master transcription factor, the tumor suppressor p53 regulates a variety of cellular processes by modulating target gene expression. Although well known as a transcriptional activator, p53 is also able to repress expression of a number of protein-coding genes. However, it remains largely unknown whether long noncoding RNA (lncRNA) gene repression is involved in the regulation of p53 function. Here, we show that p53 can transcriptionally repress expression of the lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and vice versa and that EMS can suppress p53 translation and negatively regulate p53 function. Our study reveals an important double-negative feedback loop that controls p53 activity and provides insights into the mechanisms whereby EMS promotes tumorigenesis. p53 plays a central role in tumor suppression. Emerging evidence suggests long noncoding RNA (lncRNA) as an important class of regulatory molecules that control the p53 signaling. Here, we report that the oncogenic lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and p53 mutually repress each other’s expression. EMS is negatively regulated by p53. As a direct transcriptional repression target of p53, EMS is surprisingly shown to inhibit p53 expression. EMS associates with cytoplasmic polyadenylation element-binding protein 2 (CPEB2) and thus, disrupts the CPEB2–p53 mRNA interaction. This disassociation attenuates CPEB2-mediated p53 mRNA polyadenylation and suppresses p53 translation. Functionally, EMS is able to exert its oncogenic activities, at least partially, via the CPEB2–p53 axis. Together, these findings reveal a double-negative feedback loop between p53 and EMS, through which p53 is finely controlled. Our study also demonstrates a critical role for EMS in promoting tumorigenesis via the negative regulation of p53.
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影响因子：
64.5
作者：
Huarte M;Guttman M;Feldser D;Garber M;Koziol MJ;Kenzelmann-Broz D;Khalil AM;Zuk O;Amit I;Rabani M;Attardi LD;Regev A;Lander ES;Jacks T;Rinn JL
通讯作者：
Rinn JL
DOI：
10.1016/j.bbcan.2018.06.001
发表时间：
2018-08
期刊：
Biochimica et biophysica acta. Reviews on cancer
影响因子：
--
作者：
Labuschagne CF;Zani F;Vousden KH
通讯作者：
Vousden KH
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
11.4
作者：
Chen, Hui-Feng;Hsu, Chen-Ming;Huang, Yi-Shuian
通讯作者：
Huang, Yi-Shuian
影响因子：
64.8
作者：
Dornan, D;Wertz, I;Dixit, VM
通讯作者：
Dixit, VM