Dipartimento di Patologia Sperimentale, Università di Bologna, Bologna, Italy.
Oncogene. 2011 Jul 21;30(29):3274-88. doi: 10.1038/onc.2011.48. Epub 2011 Mar 14.
Data on the relationship between ribosome biogenesis and p53 function indicate that the tumour suppressor can be activated by either nucleolar disruption or ribosomal protein defects. However, there is increasing evidence that the induction of p53 does not always require these severe cellular changes, and data are still lacking on a possible role of ribosome biogenesis in the downregulation of p53. Here, we studied the effect of the up- and downregulation of the rRNA transcription rate on p53 induction in mammalian cells. We found that a downregulation of rRNA synthesis, induced by silencing the POLR1A gene coding for the RNA polymerase I catalytic subunit, stabilised p53 without altering the nucleolar integrity in human cancer cells. p53 stabilisation was due to the inactivation of the MDM2-mediated p53 degradation by the binding of ribosomal proteins no longer used for ribosome building. p53 stabilisation did not occur when rRNA synthesis downregulation was associated with a contemporary reduction of protein synthesis. Furthermore, we demonstrated that in three different experimental models characterised by an upregulation of rRNA synthesis, cancer cells treated with insulin or exposed to the insulin-like growth factor 1, rat liver stimulated by cortisol and regenerating rat liver after partial hepatectomy, the p53 protein level was reduced due to a lowered ribosomal protein availability for MDM2 binding. It is worth noting that the upregulation of rRNA synthesis was responsible for a decreased p53-mediated response to cytotoxic stresses. These findings demonstrated that the balance between rRNA and ribosomal protein synthesis controls the function of p53 in mammalian cells, that p53 can be induced without the occurrence of severe changes of the cellular components controlling ribosome biogenesis, and that conditions characterised by an upregulated rRNA synthesis are associated with a reduced p53 response.
核糖体生物发生与 p53 功能之间关系的数据表明，肿瘤抑制因子可以通过核仁破坏或核糖体蛋白缺陷来激活。然而，越来越多的证据表明，p53 的诱导并不总是需要这些严重的细胞变化，并且关于核糖体生物发生在 p53 下调中的可能作用的数据仍然缺乏。在这里，我们研究了 rRNA 转录率的上调和下调对哺乳动物细胞中 p53 诱导的影响。我们发现，通过沉默编码 RNA 聚合酶 I 催化亚基的 POLR1A 基因下调 rRNA 合成，在人类癌细胞中稳定了 p53，而不会改变核仁的完整性。p53 的稳定是由于核糖体蛋白不再用于核糖体构建，从而与 MDM2 介导的 p53 降解结合，导致 MDM2 介导的 p53 降解失活。当 rRNA 合成下调与同期蛋白质合成减少相关时，p53 稳定不会发生。此外，我们证明在三种不同的实验模型中，rRNA 合成上调，用胰岛素或胰岛素样生长因子 1 处理的癌细胞、皮质醇刺激的大鼠肝和部分肝切除后再生的大鼠肝，p53 蛋白水平降低，因为用于 MDM2 结合的核糖体蛋白可用性降低。值得注意的是，rRNA 合成的上调导致 p53 介导的对细胞毒性应激的反应降低。这些发现表明，rRNA 和核糖体蛋白合成之间的平衡控制了 p53 在哺乳动物细胞中的功能，p53 可以在不发生控制核糖体生物发生的细胞成分发生严重变化的情况下被诱导，并且 rRNA 合成上调的条件与 p53 反应降低有关。
