Key Laboratory of Systems Biomedicine (Ministry of Education) and Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Gut. 2018 Aug;67(8):1400-1409. doi: 10.1136/gutjnl-2016-313478. Epub 2017 Jun 24.
IRTKS functions as a novel regulator of tumour suppressor p53; however, the role of IRTKS in pathogenesis of gastric cancer is unclear.
We used immunohistochemistry to detect IRTKS levels in 527 human gastric cancer specimens. We generated both -deficient and -deficient mice to observe survival time of these mice and to isolate mouse embryonic fibroblasts (MEFs) for evaluating in vivo tumorigenicity. Co-immunoprecipitation was used to study the interaction among p53, MDM2 and IRTKS, as well as the ubiquitination of p53.
IRTKS was significantly overexpressed in human gastric cancer, which was conversely associated with wild-type expression. Among patients with wild-type (n=206), those with high IRTKS expression (n=141) had a shorter survival time than those with low IRTKS (n=65) (p=0.0153). Heterozygous mice with deficiency exhibited significantly delayed tumorigenesis and an extended tumour-free survival time. MEFs without exhibited attenuated in vivo tumorigenicity. IRTKS depletion upregulated p53 and its target genes, such as and . Intriguingly, IRTKS overexpression promoted p53 ubiquitination and degradation in MEFs and gastric cancer cells. Under DNA damage conditions, IRTKS was phosphorylated at Ser331 by the activated Chk2 kinase and then dissociated from p53, along with the p53-specific E3 ubiquitin ligase MDM2, resulting in attenuated p53 ubiquitination and degradation.
IRTKS overexpression is negatively correlated with progression and overall survival time of patients with gastric cancer with wild-type p53 through promotion of p53 degradation via the ubiquitin/proteasome pathway.
IRTKS 作为一种新型抑癌蛋白 p53 的调节因子发挥作用；然而，IRTKS 在胃癌发病机制中的作用尚不清楚。
我们使用免疫组织化学方法检测了 527 例人胃癌标本中 IRTKS 的水平。我们生成了 IRTKS 缺失和 p53 缺失的小鼠，以观察这些小鼠的存活时间，并分离小鼠胚胎成纤维细胞（MEFs）以评估体内致瘤性。共免疫沉淀用于研究 p53、MDM2 和 IRTKS 之间的相互作用，以及 p53 的泛素化。
IRTKS 在人胃癌中显著过表达，与野生型 表达呈负相关。在 野生型（n=206）患者中，高 IRTKS 表达（n=141）的患者存活时间短于低 IRTKS 表达（n=65）的患者（p=0.0153）。杂合 缺失小鼠表现出明显延迟的肿瘤发生和延长的无肿瘤生存时间。缺乏 的 MEFs 表现出减弱的体内致瘤性。IRTKS 耗竭上调了 p53 及其靶基因，如 和 。有趣的是，IRTKS 过表达促进了 MEFs 和胃癌细胞中 p53 的泛素化和降解。在 DNA 损伤条件下，激活的 Chk2 激酶将 IRTKS 在 Ser331 磷酸化，然后与 p53 特异性 E3 泛素连接酶 MDM2 分离，导致 p53 泛素化和降解减弱。
IRTKS 过表达通过促进 p53 通过泛素/蛋白酶体途径降解，与野生型 p53 的胃癌患者的进展和总体生存时间呈负相关。
