The ribosomal protein S26 regulates p53 activity in response to DNA damage
The ribosomal protein S26 regulates p53 activity in response to DNA damage
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核糖体蛋白 S26 调节 p53 活性以应对 DNA 损伤
DOI：
10.1038/onc.2013.170
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发表时间：
2014-04-24
期刊：
影响因子：
8
通讯作者：
Tang, J.
中科院分区：
文献类型：
--
作者：
Cui, D.;Li, L.;Tang, J.
核糖体蛋白已经成为Mdm 2-p53反馈环的新型调节剂，特别是在核糖体应激的背景下。RPS 26是最近发现的Diamond-Blackfan贫血相关的核糖体蛋白，其在p53激活中的作用尚未被探索。在这项研究中，我们发现RPS 26的敲低通过RPL 11依赖性机制诱导p53稳定和激活，导致p53依赖性细胞生长抑制。此外，RPS 26具有与Mdm 2相互作用的能力，并抑制Mdm 2介导的p53泛素化，其导致p53在过表达时稳定。重要的是，我们发现RPS 26敲低损害了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，在RPS 26敲低后，DNA损伤诱导的p53向其靶基因启动子的募集和p53乙酰化都大大减少。此外，RPS 26可以独立于Mdm 2与p53相互作用，并与p53和p300共存于复合物中。这些数据通过直接影响p53转录活性确立了RPS 26在DNA损伤反应中的作用，并表明RPS 26在p53激活的不同情况下起着独特的作用。我们的发现也暗示p53转录活性控制作为一个重要的机制p53的核糖体蛋白的调节。
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.