Long non-coding RNA TILR constitutively represses TP53 and apoptosis in lung cancer
Long non-coding RNA TILR constitutively represses TP53 and apoptosis in lung cancer
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DOI：
10.1038/s41388-022-02546-w
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发表时间：
2022-12-15
期刊：
影响因子：
8
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
--
作者：
Iwai, Mika;Kajino, Taisuke;Takahashi, Takashi
非编码RNA在与肺癌发展相关的许多功能中具有不可或缺的调节作用。在这里，我们报告了一种新的lncRNA的鉴定，称为TP53抑制lncRNA（TILR），它被发现作为一个组成性的p53表达的负调控因子，包括激活下游基因，如p21和MDM 2，诱导细胞凋亡。TILR相关蛋白的蛋白质组学搜索显示与PCBP2的关联，而TILR的中间部分被发现是PCBP2和p53 mRNA结合所需的。此外，PCBP2的耗竭导致TILR沉默的表型模仿效应。TILR还显示以转录后方式抑制p53表达，以及通过涉及p53和范可尼贫血途径基因的正反馈环。两者合计，本研究结果清楚地表明，TILR组成型抑制p53的表达与PCBP2合作，从而保持p53的转录活性在足够低的水平，以避免假的凋亡诱导。
Non-coding RNAs have an integral regulatory role in numerous functions related to lung cancer development. Here, we report identification of a novel lncRNA, termed TP53-inhibitinglncRNA (TILR), which was found to function as a constitutive negative regulator of p53 expression, including activation of downstream genes such as p21 and MDM2, and induction of apoptosis. A proteomic search for TILR-associated proteins revealed an association with PCBP2, while the mid-portion of TILR was found to be required for both PCBP2 and p53 mRNA binding. In addition, depletion of PCBP2 resulted in phenocopied effects of TILR silencing. TILR was also shown to suppress p53 expression in a post-transcriptional manner, as well as via a positive feedback loop involving p53 and Fanconi anemia pathway genes. Taken together, the present findings clearly demonstrate that TILR constitutively inhibits p53 expression in cooperation with PCBP2, thus maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.