Regulation of miR-186-YY1 axis by the p53 translational isoform ∆40p53: implications in cell proliferation

We have earlier shown that p53-FL and its translational isoform ∆40p53 are differentially regulated. In this study, we have investigated the cellular effect of ∆40p53 regulation on downstream gene expression, specifically miRNAs. Interestingly, ∆40p53 showed antagonistic regulation of miR-186-5p as compared to either p53 alone or a combination of both the isoforms. We have elucidated the miR-186-5p mediated effect of ∆40p53 in cell proliferation. Upon expression of ∆40p53, we observed a significant decrease in YY1 levels, an established target of miR-186-5p, which is involved in cell proliferation. Further assays with anti-miR-186 established the interdependence of ∆40p53− miR-186-5p−YY1− cell proliferation. The results unravel a new dimension toward the understanding of ∆40p53 functions, which seems to regulate cellular fate independent of p53FL.我们此前已证实，全长p53（p53-FL）及其翻译异构体∆40p53的调控模式存在显著差异。本研究针对∆40p53调控下游基因表达（尤其是微小RNA（miRNAs））的细胞效应展开了系统探究。值得注意的是，相较于单独的p53或两种异构体联合表达的情况，∆40p53对miR-186-5p呈现出拮抗调控作用。我们进一步阐明了∆40p53通过miR-186-5p介导的细胞增殖效应：在过表达∆40p53后，我们观察到作为miR-186-5p已知靶标且参与细胞增殖过程的YY1的表达水平显著下调。后续通过抗miR-186开展的实验验证，进一步证实了∆40p53–miR-186-5p–YY1通路与细胞增殖之间的相互依赖关系。本研究结果为解析∆40p53的功能提供了全新维度，表明其可独立于p53-FL调控细胞命运。