Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Oncogene. 2020 Mar;39(10):2202-2211. doi: 10.1038/s41388-019-1133-7. Epub 2019 Dec 11.
p53 is one of the most important tumor suppressor genes, and the exploration of p53-target genes is important for elucidation of its functional mechanisms. In this study, we identified Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) as a direct target of p53 through ChIP-sequencing analysis. Activated p53 protein was found to bind to two distinct sites in the ARVCF gene, resulting in induction of ARVCF expression at both the mRNA and protein levels. We revealed that the knockdown of ARVCF inhibited p53-induced apoptosis. Interestingly, ARVCF interacted with hnRNPH2, which is involved in pre-mRNA splicing, and ARVCF knockdown induced dynamic changes in alternative splicing patterns. These results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Thus, we demonstrated that the induction of ARVCF expression contributed to the tumor suppressive function of p53. Recently, it has been reported that many tumors have thousands of alternative splicing events that are not detectable in normal samples. ARVCF may play a role in alternative splicing events in cancer and may provide clues to explore novel approaches for cancer diagnosis and therapy.
p53 是最重要的肿瘤抑制基因之一，探索 p53 的靶基因对于阐明其功能机制非常重要。在这项研究中，我们通过 ChIP-seq 分析鉴定出盔蛋白重复基因缺失的 velo-心-面综合征（ARVCF）是 p53 的直接靶基因。激活的 p53 蛋白被发现与 ARVCF 基因中的两个不同位点结合，导致 ARVCF 在 mRNA 和蛋白水平的表达诱导。我们揭示了 ARVCF 的敲低抑制了 p53 诱导的细胞凋亡。有趣的是，ARVCF 与参与 pre-mRNA 剪接的 hnRNPH2 相互作用，ARVCF 的敲低诱导了特定基因剪接模式的动态变化。这些结果表明，p53 诱导的 ARVCF 通过特定基因剪接的改变间接但不是直接调节 p53 靶标选择性。因此，我们证明了 ARVCF 表达的诱导有助于 p53 的肿瘤抑制功能。最近有报道称，许多肿瘤中有数千种在正常样本中检测不到的可变剪接事件。ARVCF 可能在癌症中的可变剪接事件中发挥作用，并可能为探索癌症诊断和治疗的新方法提供线索。
