Cui D, Li L, Lou H, Sun H, Ngai S-M, Shao G, Tang J
1] State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China [2] Department of Basic Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing, China.
1] State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China [2] College of Biological Sciences, China Agricultural University, Beijing, China.
Oncogene. 2014 Apr 24;33(17):2225-35. doi: 10.1038/onc.2013.170. Epub 2013 Jun 3.
Ribosomal proteins have emerged as novel regulators of the Mdm2-p53 feedback loop, especially in the context of ribosomal stress. RPS26 is a recently identified Diamond-Blackfan Anemia-related ribosomal protein and its role in p53 activation has not been previously explored. In this study we found knockdown of RPS26 induced p53 stabilization and activation via a RPL11-dependent mechanism, resulting in p53-dependent cell growth inhibition. Moreover, RPS26 has the ability to interact with Mdm2 and inhibits Mdm2-mediated p53 ubiquitination that leads to p53 stabilization upon overexpression. Importantly, we discovered that RPS26 knockdown impaired p53's ability to transcriptionally activate its target genes in response to DNA damage, without affecting its stability. Accordingly, the cells lost the ability to induce G2/M cell cycle arrest. We further found that upon RPS26 knockdown, the DNA damage induced recruitment of p53 to the promoters of its target genes and p53 acetylation were both greatly reduced. In addition, RPS26 can interact with p53 independent of Mdm2 and coexist in a complex with p53 and p300. These data establish a role of RPS26 in DNA damage response by directly influencing p53 transcriptional activity, and suggest that RPS26 acts distinctively in different scenarios of p53 activation. Our finding also implicates p53 transcriptional activity control as an important mechanism of p53 regulation by ribosomal proteins.
核糖体蛋白已成为Mdm2-p53反馈环的新型调节因子，尤其是在核糖体应激的情况下。RPS26是最近鉴定出的与钻石-黑范贫血相关的核糖体蛋白，其在p53激活中的作用此前尚未被探索。在本研究中，我们发现敲低RPS26通过依赖RPL11的机制诱导p53稳定和激活，导致p53依赖的细胞生长抑制。此外，RPS26具有与Mdm2相互作用并抑制Mdm2介导的p53泛素化的能力，过表达时会导致p53稳定。重要的是，我们发现敲低RPS26会损害p53在DNA损伤时转录激活其靶基因的能力，而不影响其稳定性。因此，细胞失去了诱导G2/M细胞周期停滞的能力。我们进一步发现，敲低RPS26后，DNA损伤诱导的p53募集到其靶基因启动子以及p53乙酰化均大大减少。此外，RPS26可以独立于Mdm2与p53相互作用，并与p53和p300共存于一个复合物中。这些数据通过直接影响p53转录活性确立了RPS26在DNA损伤反应中的作用，并表明RPS26在p53激活的不同情况下发挥独特作用。我们的发现还暗示p53转录活性控制是核糖体蛋白调节p53的重要机制。
