Low expression of certain ribosomal proteins leads to the inactivation of p53, which is mediated mainly by RPL5 or RPL11 (ribosomal protein L11). It is also unknown what mechanisms drive aberrant ribosomal proteins expression in tumor. SRBD1 (S1 RNA‐binding domain 1), as a highly conserved RNA‐binding protein, is lowly expressed in glioma tissues and correlated with glioma prognosis. In this study, we observed that SRBD1 was closely related to p53 signaling. The upregulation of SRBD1 elevated p53 levels, thereby activating the p53 signaling pathway. As an RNA bind protein, SRBD1 could bind to the 5′‐UTR of target genes and regulate RNA translation. We further conducted RNA immunoprecipitation using anti‐SRDB1 antibody and noticed 29 hub RNA, including RPL11. RPL11 could inhibit MDM2‐mediated p53 ubiquitination. SRBD1 upregulation promoted RPL11 binding to MDM2 via elevating RPL11 protein levels, which in turn activated the p53 signaling. Disrupting the p53 signaling blocked SRBD1‐induced glioma suppression. In mouse xenograft model, SRBD1 ectopic expression was effective in reducing the total M2 tumor‐associated macrophages (TAMs) density and suppressed glioma tumor growth. In summary, these data show that SRBD1 has a critical role in inhibition of glioma tumor growth and M2 macrophage polarization, and targeting RPL11‐MDM2‐p53 signaling may be an effective strategy to improve therapy and survival for glioma patients.

中文翻译：

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SRBD1 通过 RPL11-MDM2-p53 通路调节胶质瘤中的细胞周期、细胞凋亡和 M2 巨噬细胞极化


某些核糖体蛋白的低表达会导致 p53 失活，这主要由 RPL5 或 RPL11（核糖体蛋白 L11）介导。目前还不清楚是什么机制驱动肿瘤中核糖体蛋白的异常表达。 SRBD1（S1 RNA结合域1）作为一种高度保守的RNA结合蛋白，在胶质瘤组织中低表达，与胶质瘤预后相关。在这项研究中，我们观察到SRBD1与p53信号密切相关。 SRBD1 的上调提高了 p53 水平，从而激活 p53 信号通路。作为一种RNA结合蛋白，SRBD1可以与靶基因的5'-UTR结合并调节RNA翻译。我们进一步使用抗 SRDB1 抗体进行 RNA 免疫沉淀，发现了 29 个 hub RNA，包括 RPL11。 RPL11 可以抑制 MDM2 介导的 p53 泛素化。 SRBD1 上调通过提高 RPL11 蛋白水平促进 RPL11 与 MDM2 结合，进而激活 p53 信号传导。破坏 p53 信号传导可阻止 SRBD1 诱导的神经胶质瘤抑制。在小鼠异种移植模型中，SRBD1异位表达可有效降低M2肿瘤相关巨噬细胞（TAM）的总密度并抑制神经胶质瘤的生长。总之，这些数据表明 SRBD1 在抑制神经胶质瘤生长和 M2 巨噬细胞极化方面具有关键作用，靶向 RPL11-MDM2-p53 信号传导可能是改善神经胶质瘤患者治疗和生存的有效策略。