Background and objectives IRTKS functions as a novel regulator of tumour suppressor p53; however, the role of IRTKS in pathogenesis of gastric cancer is unclear. Design We used immunohistochemistry to detect IRTKS levels in 527 human gastric cancer specimens. We generated both IRTKS-deficient and p53-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. Results IRTKS was significantly overexpressed in human gastric cancer, which was conversely associated with wild-type p53 expression. Among patients with wild-type p53 (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 p53 +/− mice with IRTKS deficiency exhibited significantly delayed tumorigenesis and an extended tumour-free survival time. p53+/− MEFs without IRTKS exhibited attenuated in vivo tumorigenicity. IRTKS depletion upregulated p53 and its target genes, such as BAX and p21. 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. Conclusion 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.

中文翻译：

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IRTKS与胃癌患者的进展和生存时间相关

背景和目的 IRTKS 作为肿瘤抑制因子 p53 的新型调节剂发挥作用；然而，IRTKS 在胃癌发病机制中的作用尚不清楚。设计 我们使用免疫组织化学检测 527 份人类胃癌标本中的 IRTKS 水平。我们生成了 IRTKS 缺陷型和 p53 缺陷型小鼠，以观察这些小鼠的存活时间并分离小鼠胚胎成纤维细胞 (MEF) 以评估体内致瘤性。免疫共沉淀用于研究 p53、MDM2 和 IRTKS 之间的相互作用以及 p53 的泛素化。结果 IRTKS 在人胃癌中显着过表达，这与野生型 p53 表达呈负相关。在野生型 p53 患者 (n=206) 中，高 IRTKS 表达​​患者 (n=141) 的生存时间比低 IRTKS 患者 (n=65) (p=0.0153) 短。具有 IRTKS 缺陷的杂合 p53 +/- 小鼠表现出显着延迟的肿瘤发生和延长的无肿瘤存活时间。没有 IRTKS 的 p53+/- MEF 表现出减弱的体内致瘤性。IRTKS 耗竭上调 p53 及其靶基因，如 BAX 和 p21。有趣的是，IRTKS 过表达促进了 MEF 和胃癌细胞中 p53 泛素化和降解。在 DNA 损伤条件下，IRTKS 在 Ser331 处被活化的 Chk2 激酶磷酸化，然后与 p53 特异性 E3 泛素连接酶 MDM2 一起从 p53 上解离，导致 p53 泛素化和降解减弱。结论 IRTKS过表达通过泛素/蛋白酶体途径促进p53降解，与野生型p53胃癌患者的进展和总生存时间呈负相关。