Institute of Clinical Molecular Biology and Tumour Genetics, Center of Integrated Protein Science, Munich 85758, Germany.
J Biol Chem. 2010 Feb 26;285(9):6364-70. doi: 10.1074/jbc.M109.054734. Epub 2010 Jan 7.
The p53 tumor suppressor pathway is activated by defective ribosome synthesis. Ribosomal proteins are released from the nucleolus and block human double minute-2 (Hdm2) that targets p53 for degradation. However, it remained elusive how abrogation of individual rRNA processing pathways contributes to p53 stabilization. Here, we show that selective inhibition of 18 S rRNA processing provokes accumulation of p53 as efficiently as abrogated 28 S rRNA maturation. We describe hUTP18 as a novel mammalian rRNA processing factor that is specifically involved in 18 S rRNA production. hUTP18 was essential for the cleavage of the 5'-external transcribed spacer leader sequence from the primary polymerase I transcript, but was dispensable for rRNA transcription. Because maturation of the 28 S rRNA was unaffected in hUTP18-depleted cells, our results suggest that the integrity of both the 18 S and 28 S rRNA synthesis pathways can be monitored independently by the p53 pathway. Interestingly, accumulation of p53 after hUTP18 knock down required the ribosomal protein L11. Therefore, cells survey the maturation of the small and large ribosomal subunits by separate molecular routes, which may merge in an L11-dependent signaling pathway for p53 stabilization.
p53 肿瘤抑制因子途径被异常核糖体合成激活。核糖体蛋白从核仁中释放出来并阻止靶向 p53 降解的人双微体 2（Hdm2）。然而，尚不清楚个体 rRNA 加工途径的缺失如何导致 p53 稳定。在这里，我们表明，选择性抑制 18S rRNA 加工与阻断 28S rRNA 成熟一样有效地引起 p53 的积累。我们将 hUTP18 描述为一种新型哺乳动物 rRNA 加工因子，它专门参与 18S rRNA 的产生。hUTP18 对于从初级聚合酶 I 转录本中从 5'-外部转录间隔区引导序列切割是必需的，但对于 rRNA 转录是可有可无的。由于在 hUTP18 耗尽的细胞中 28S rRNA 的成熟不受影响，因此我们的结果表明，p53 途径可以独立监测 18S 和 28S rRNA 合成途径的完整性。有趣的是，hUTP18 敲低后 p53 的积累需要核糖体蛋白 L11。因此，细胞通过单独的分子途径来检测小和大亚基核糖体的成熟，这可能在依赖于 L11 的 p53 稳定信号通路中合并。
