Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Cell Rep. 2017 Sep 5;20(10):2408-2423. doi: 10.1016/j.celrep.2017.08.041.
Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels.
在正常情况下，p53 的基础水平受到严格抑制。破坏这种调节会导致 p53 水平升高，从而诱导细胞周期停滞、细胞凋亡和肿瘤抑制。在这里，我们报告了一种核内 p53 调节的长非编码 RNA（我们称之为 PURPL）抑制基础 p53 水平的情况。在结直肠癌细胞中靶向耗尽 PURPL 会导致基础 p53 水平升高，并在细胞培养和小鼠异种移植中诱导生长缺陷。PURPL 与 MYBBP1A 结合，MYBBP1A 是一种与 p53 结合并稳定 p53 的蛋白质，抑制 p53-MYBBP1A 复合物的形成。在没有 PURPL 的情况下，MYBBP1A 与 p53 相互作用并稳定 p53。沉默 MYBBP1A 可显著挽救 PURPL 缺陷细胞中的基础 p53 水平和增殖，表明 MYBBP1A 介导了 PURPL 在调节 p53 中的作用。这些结果揭示了 p53-PURPL 自动反馈调节环，并证明了 PURPL 在维持基础 p53 水平中的作用。
