SRBD1 Regulates the Cell Cycle, Apoptosis, and M2 Macrophage Polarization via the RPL11-MDM2-p53 Pathway in Glioma

IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES
Hongfu Chen, Shuping Gao, Peng Wang, Manyi Xie, Hui Zhang, Yuechao Fan, Er Nie, Qing Lan
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引用次数: 0

Abstract

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.

SRBD1通过胶质瘤中的RPL11-MDM2-p53通路调控细胞周期、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,而这主要是由 RPL5 或 RPL11(核糖体蛋白 L11)介导的。目前还不清楚肿瘤中核糖体蛋白异常表达的驱动机制。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,并与胶质瘤预后相关。在本研究中,我们观察到 SRBD1 与 p53 信号转导密切相关。SRBD1的上调会提高p53的水平,从而激活p53信号通路。作为一种 RNA 结合蛋白,SRBD1 可与靶基因的 5′-UTR 结合并调控 RNA 翻译。我们进一步利用抗SRDB1抗体进行了RNA免疫沉淀,发现了29个中枢RNA,其中包括RPL11。RPL11可以抑制MDM2介导的p53泛素化。SRBD1的上调通过提高RPL11蛋白水平促进了RPL11与MDM2的结合,进而激活了p53信号传导。破坏p53信号转导可阻断SRBD1诱导的胶质瘤抑制作用。在小鼠异种移植模型中,SRBD1异位表达能有效降低M2肿瘤相关巨噬细胞(TAMs)的总密度,抑制胶质瘤肿瘤的生长。总之,这些数据表明,SRBD1在抑制胶质瘤肿瘤生长和M2巨噬细胞极化中具有关键作用,靶向RPL11-MDM2-p53信号转导可能是改善胶质瘤患者治疗和生存的有效策略。
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来源期刊
Environmental Toxicology
Environmental Toxicology 环境科学-毒理学
CiteScore
7.10
自引率
8.90%
发文量
261
审稿时长
4.5 months
期刊介绍: The journal publishes in the areas of toxicity and toxicology of environmental pollutants in air, dust, sediment, soil and water, and natural toxins in the environment.Of particular interest are: Toxic or biologically disruptive impacts of anthropogenic chemicals such as pharmaceuticals, industrial organics, agricultural chemicals, and by-products such as chlorinated compounds from water disinfection and waste incineration; Natural toxins and their impacts; Biotransformation and metabolism of toxigenic compounds, food chains for toxin accumulation or biodegradation; Assays of toxicity, endocrine disruption, mutagenicity, carcinogenicity, ecosystem impact and health hazard; Environmental and public health risk assessment, environmental guidelines, environmental policy for toxicants.
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