Roles of p27^<Kip1> on metastasis of human gastric cancers

泛素-蛋白酶体途径是控制细胞蛋白数量水平的关键系统。该途径不仅负责短寿命蛋白的降解，还负责肿瘤抑制因子、转录因子和细胞周期蛋白的降解。泛素蛋白连接酶决定了泛素化的底物特异性。在本研究中，我们分析了Cdk抑制蛋白p27^<Kip1>蛋白水解降解的分子机制。此外，我们试图通过实验证明p27^<Kip1>的下调促进了肿瘤的进展。在这项研究中，我们发现Cks1是用于p27降解的SCF-Skp2泛素连接酶的一个亚组分，在翻译后受泛素-蛋白酶体途径的调控。我们还发现Cks1在人类肺癌中高表达。因此，Cks1蛋白降解的改变被认为促进了癌症的生长和恶性。接下来，我们利用p27^<Kip1>表达下调的模型细胞系，通过实验证明p27^<Kip1>的下调促进了淋巴结小鼠的肿瘤进展。

Ubiquitin-proteasome pathway is a key system that controls cellular levels of number of proteins. This pathway is responsible not only for the degradation of short-lived proteins but also tumor suppressors, transcription factors and cell cycle proteins. Ubiquitin-protein ligases determine the substrate specificity of ubiquitination. In this study, we analyzed the molecular mechanisms of proteolytic degradation of Cdk inhibitory protein p27^<Kip1>. Furthermore, we tried to experimentally demonstrate that down-regulation of p27^<Kip1> promoted tumor progression.In this study, we found that Cks1, a subcomponent of SCF-Skp2 ubiquitin ligase for p27-degradation, was post-translationally regulated by ubiquitin-proteasome pathway. We also found high expression of Cks1 in human lung cancers. Therefore, altered degradation of Cks1 proteins is thought to promote growth and malignancy of cancer. Next, we experimentally demonstrate that down-regulation of p27^<Kip1> promoted tumor progression in node mice using the model cell lines which shawed down-regulated expression of p27^<Kip1>.