Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here, we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 may be attributed to its negative regulation of uL18, leading to p53 inactivation.

中文翻译：

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SPIN1通过阻断人类癌症中的uL18（通用大核糖体亚基蛋白18）-MDM2-p53通路促进肿瘤发生

核糖体蛋白 (RPs) 在调节 MDM2-p53 通路中起重要作用。然而，人们对 RP 的上游监管机构知之甚少。在这里，我们将 SPIN1 (Spindlin 1) 鉴定为人类 RPL5/uL18 的新结合伙伴，这对该途径很重要。SPIN1 消融激活 p53，抑制细胞生长，降低克隆形成能力，并诱导人类癌细胞凋亡。从机制上讲，SPIN1 将 uL18 隔离在核仁中，阻止它与 MDM2 相互作用，从而减轻 uL18 介导的 MDM2 泛素连接酶对 p53 活性的抑制。SPIN1 缺乏会增加无核糖体的 uL18 和 uL5（人 RPL11），这是 SPIN1 消耗诱导的 p53 激活所必需的。对癌症基因组数据库的分析表明，SPIN1 在几种人类癌症中高度表达，并且其过表达与癌症患者的不良预后呈正相关。总之，我们的研究结果表明，SPIN1 的致癌特性可能归因于其对 uL18 的负调控，导致 p53 失活。