Hubalek Michael M, Widschwendter Andreas, Erdel Martin, Gschwendtner Andreas, Fiegl Heidi M, Müller Hannes M, Goebel Georg, Mueller-Holzner Elisabeth, Marth Christian, Spruck Charles H, Reed Steven I, Widschwendter Martin
Department of Obstetrics and Gynecology, Innsbruck University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria.
Oncogene. 2004 May 20;23(23):4187-92. doi: 10.1038/sj.onc.1207560.
Deregulation of cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2), has been associated with a broad spectrum of human malignancies. Yet the mechanism linking abnormal cyclin E expression to carcinogenesis is largely unknown. The gene encoding the F-box protein hCdc4, a key component of the molecular machinery that targets cyclin E for degradation, is frequently mutated in endometrial cancer, leading to deregulation of cyclin E expression. Here we show that hCDC4 gene mutation and hyperphosphorylation of cyclin E, a parameter that usually correlates with hCDC4 mutation, have a strong statistically significant association with polypoidy and aneuploidy in endometrial cancer. On the contrary, elevated expression of cyclin E by itself was not significantly correlated with polyploidy or aneuploidy when tumors of similar grade are evaluated. These data suggest that impairment of cell cycle regulated proteolysis of cyclin E may be linked to carcinogenesis by promoting genomic instability.
细胞周期蛋白E是细胞周期蛋白依赖性激酶2（Cdk2）的激活剂，其失调与多种人类恶性肿瘤相关。然而，将异常细胞周期蛋白E表达与致癌作用联系起来的机制在很大程度上尚不清楚。编码F-box蛋白hCdc4的基因是将细胞周期蛋白E靶向降解的分子机制的关键组成部分，该基因在子宫内膜癌中经常发生突变，导致细胞周期蛋白E表达失调。在这里，我们表明hCDC4基因突变以及细胞周期蛋白E的过度磷酸化（这一参数通常与hCDC4突变相关）与子宫内膜癌中的息肉样病变和非整倍体具有很强的统计学显著关联。相反，在评估相似分级的肿瘤时，细胞周期蛋白E自身的表达升高与多倍体或非整倍体并无显著相关性。这些数据表明，细胞周期蛋白E的细胞周期调节性蛋白水解受损可能通过促进基因组不稳定与致癌作用相关联。
