Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
Oncogene. 2011 Apr 14;30(15):1798-811. doi: 10.1038/onc.2010.569. Epub 2010 Dec 20.
Several ribosomal proteins regulate p53 function by modulating MDM2. We recently found that RPS27L, a RPS27-like protein, is a direct p53-inducible target. Here we showed that RPS27 itself is a p53-repressible target. Furthermore, the N-terminal region of either RPS27L or RPS27 binds to MDM2 on the central acidic domain of MDM2. RPS27L or RPS27 forms an in vivo triplex with MDM2-p53 and competes with p53 for MDM2 binding. Similar to p53, RPS27L, but not RPS27, is a short-lived protein and a novel MDM2 substrate. Degradation of RPS27L requires the RING or acidic domain of MDM2. Ectopic expression of RPS27L or RPS27 inhibits MDM-2-mediated p53 ubiquitination and increases p53 levels by extending p53 protein half-life, whereas siRNA silencing of RPS27L decreases p53 levels by shortening p53 half-life, with a corresponding reduction in p53 transcription activity. RPS27L is mainly localized in the cytoplasm, but upon p53-activating signals, a portion of RPS27L shuttled to the nucleoplasm where it colocalizes with MDM2. Both the cytoplasmic and the nuclear p53, induced by ribosomal stress, were reduced upon RPS27L silencing. Our study reveals a multilevel interplay between RPS27L/S27 and p53-MDM2 axis, with RPS27L functioning as a p53 target, a MDM2 substrate and a p53 regulator.
几种核糖体蛋白通过调节 MDM2 来调节 p53 功能。我们最近发现，RPS27L（一种与 RPS27 相似的蛋白质）是一个直接的 p53 诱导靶标。在这里，我们表明 RPS27 本身是一个 p53 抑制靶标。此外，RPS27L 或 RPS27 的 N 端区域与 MDM2 的中央酸性结构域结合。RPS27L 或 RPS27 与 MDM2-p53 形成体内三联体，并与 p53 竞争 MDM2 结合。与 p53 类似，RPS27L 而不是 RPS27 是一种短寿命蛋白质和新型 MDM2 底物。RPS27L 的降解需要 MDM2 的 RING 或酸性结构域。RPS27L 或 RPS27 的异位表达抑制 MDM-2 介导的 p53 泛素化，并通过延长 p53 蛋白半衰期来增加 p53 水平，而 RPS27L 的 siRNA 沉默通过缩短 p53 半衰期来降低 p53 水平，从而相应降低 p53 转录活性。RPS27L 主要定位于细胞质中，但在 p53 激活信号下，一部分 RPS27L 穿梭到核质中，与 MDM2 共定位。核糖体应激诱导的细胞质和核内 p53 在 RPS27L 沉默后均减少。我们的研究揭示了 RPS27L/S27 和 p53-MDM2 轴之间的多层次相互作用，其中 RPS27L 作为 p53 靶标、MDM2 底物和 p53 调节剂发挥作用。
