Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul, Republic of Korea.
Oncogene. 2011 Jul 28;30(30):3317-27. doi: 10.1038/onc.2011.47. Epub 2011 Mar 7.
The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.
细胞中最大的能量消费者是核糖体生物发生，其异常会在人类中引发各种疾病。最近已经揭示，p53 的诱导以及细胞周期停滞与异常核糖体生物发生有关，但确切的机制仍不清楚。在这项研究中，我们发现异常的核糖体生物发生激活了两条平行的细胞通路，c-Myc 和 ASK1/p38，这导致了 p53 的诱导和 G1 期阻滞。c-Myc 通过 rpL11 介导的 HDM2 抑制稳定 p53，而 ASK1/p38 通过丝氨酸 15 和 33 的磷酸化激活 p53。我们的研究证明了这两条通路与 p53 诱导之间的关系。通过抑制任何一条通路，核糖体应激引起的变化，如 p53 的诱导和 G1 期阻滞，完全消失。这些发现表明，c-Myc 和 ASK1/p38 通过控制 p53 蛋白的稳定性和活性，对异常核糖体生物发生形成一种监测机制。
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