Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Division of Molecular Diagnostics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.
Oncogene. 2023 Jan;42(5):364-373. doi: 10.1038/s41388-022-02546-w. Epub 2022 Dec 15.
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-inhibiting lncRNA (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.
非编码 RNA 在与肺癌发生相关的许多功能中具有重要的调节作用。在这里，我们报告了一种新型 lncRNA 的鉴定，称为 TP53 抑制 lncRNA（TILR），它被发现作为 p53 表达的组成性负调节剂起作用，包括激活下游基因，如 p21 和 MDM2，并诱导细胞凋亡。对 TILR 相关蛋白的蛋白质组学搜索发现与 PCBP2 有关，而 TILR 的中部被发现需要与 PCBP2 和 p53 mRNA 结合。此外，PCBP2 的耗竭导致 TILR 沉默的表型模拟效应。TILR 还被证明以转录后方式以及涉及 p53 和范可尼贫血途径基因的正反馈环抑制 p53 表达。总之，这些发现清楚地表明，TILR 与 PCBP2 合作，在转录水平上持续抑制 p53 表达，从而使 p53 转录活性保持在足够低的水平，以避免虚假的细胞凋亡诱导。
