SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer.
SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer.
复制标题
作者：
Fang Z;Cao B;Liao JM;Deng J;Plummer KD;Liao P;Liu T;Zhang W;Zhang K;Li L;Margolin D;Zeng SX;Xiong J;Lu H
核糖体蛋白（RPs）在调节MDM 2-p53通路中起重要作用。然而，对RP的上游调节器知之甚少。在这里，我们确定SPIN 1（Spindlin 1）作为一种新的结合伴侣的人RPL 5/uL 18，这是重要的这一途径。SPIN 1消融激活p53，抑制细胞生长，降低克隆形成能力，并诱导人癌细胞凋亡。从机制上讲，SPIN 1将uL 18隔离在核仁中，防止其与MDM 2相互作用，从而减轻uL 18介导的对MDM 2泛素连接酶活性对p53的抑制。SPIN 1缺乏增加了无核糖体的uL 18和uL 5（人RPL 11），这是SPIN 1缺失诱导的p53激活所必需的。对癌症基因组数据库的分析表明，SPIN 1在多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正相关。总之，我们的研究结果表明，SPIN 1的致癌特性可能归因于其对uL 18的负调控，导致p53失活。
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.