Oncogenic role of APC/C ubiquitin ligase inhibitor, Emi1

细胞周期中检查点和细胞分裂的异常被认为是癌症发生的触发因素。APC/C泛素连接酶复合体调节细胞分裂过程中许多关键分子的蛋白质水平。APC/C的抑制剂EMI1可抑制S期至M期开始的APC/C活性。在本研究中，我们发现APC/C抑制剂Emi1在肿瘤细胞系和头颈癌病例中经常过表达。此外，我们发现了一种在细胞周期进程中结构性表达Emi1的癌细胞株。在该细胞系中，Emi1的Ser310和Thr315通过ERK-RSK途径被磷酸化，这种磷酸化抑制了泛素介导的蛋白降解。Emi1的结构性表达抑制了细胞周期进程中的APC/C活性，并诱导了APC/C底物的过度表达。综上所述，降解缺陷导致的Emi1过度表达导致了APC/C活性的结构性抑制，参与了细胞周期的异常调节和肿瘤的发生。

The abnormality of checkpoint and cell division during cell cycle is thought to be a trigger of carcinogenesis. APC/C ubiquitin ligase complex regulates the protein level of many key molecules for cell division. Emi1, an inhibitor of APC/C, inhibits APC/C activity from S phase to the beginning of M phase. In the present study, we found that APC/C inhibitor, Emi1 was frequently overexpressed in cancer cell lines and head and neck cancer cases. Moreover, we found a cancer cell line that constitutively expressed Emi1 during cell cycle progression. In this cell line, Ser310 and Thr315 of Emi1 were phosphorylated by ERK-RSK pathway and this phosphorylation inhibited ubiquitin-mediated proteolysis. Constitutive Emi1 expression inhibited APC/C activity during cell cycle progression and induced overexpression of APC/C substrates.In summary, Emi1 overexpression caused by the defects of degradation induced the constitutive inhibition of APC/C activity and was involved in abnormal regulation of cell cycle and carcinogenesis.