Cyclin A1 is a p53-induced gene that mediates apoptosis, G2/M arrest, and mitotic catastrophe in renal, ovarian, and lung carcinoma cells
Cyclin A1 is a p53-induced gene that mediates apoptosis, G2/M arrest, and mitotic catastrophe in renal, ovarian, and lung carcinoma cells
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DOI：
10.1007/s00018-006-5521-5
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发表时间：
2006-06-01
影响因子：
8
通讯作者：
Maxwell, S. A.
中科院分区：
文献类型：
--
作者：
Rivera, A.;Mavila, A.;Maxwell, S. A.
我们首次通过对对p53敏感和耐药的肿瘤细胞进行基因表达谱分析，将细胞周期蛋白A1鉴定为p53诱导的基因[Maxwell S.A.和Davis G.E.(2000)Proc。娜塔莉。阿卡德。SCI。美国97,13009-13014]。我们发现，细胞周期蛋白A1可以诱导H1299非小细胞肺癌细胞、TOV-21G卵巢癌细胞或786-0肾癌细胞发生G2期细胞周期停滞、多倍体、凋亡和有丝分裂灾难。在Cyclin A1诱导的细胞中观察到比GFP对照诱导的细胞中更多的CDK1蛋白和激酶活性。因此，细胞周期蛋白A1可能通过CDK1的非程序性或不适当的激活来介导细胞凋亡和有丝分裂灾难。与相应的正常肾组织相比，2例表达突变型P53的原发性肾细胞癌细胞周期蛋白A1表达降低或缺失。此外，肾癌来源的突变体p53s在诱导p53缺失细胞中细胞周期蛋白A1的表达方面存在缺陷。在依托泊苷治疗的肿瘤细胞中，细胞周期蛋白A1表达上调，而不是细胞周期蛋白A2表达上调，肿瘤细胞经历了p53依赖的凋亡和有丝分裂灾难。强迫上调细胞周期蛋白A2并不能诱导细胞凋亡。这些数据表明，细胞周期蛋白A1在P53依赖的细胞凋亡和G2期停滞中起下游作用。
We were the first to identify cyclin A1 as a p53-induced gene by cDNA expression profiling of p53-sensitive and -resistant tumor cells [Maxwell S. A. and Davis G. E. (2000) Proc. Natl. Acad. Sci. USA 97, 13009-13014]. We show here that cyclin A1 can induce G2 cell cycle arrest, polyploidy, apoptosis, and mitotic catastrophe in H1299 non-small cell lung, TOV-21G ovarian, or 786-0 renal carcinoma cells. More cdk1 protein and kinase activities were observed in cyclin A1-induced cells than in GFP control-induced cells. Thus, cyclin A1 might mediate apoptosis and mitotic catastrophe through an unscheduled or inappropriate activation of cdk1. Two primary renal cell carcinomas expressing mutated p53 exhibited reduced or absent expression of cyclin A1 relative to the corresponding normal tissue. Moreover, renal carcinoma-derived mutant p53s were deficient in inducing cyclin A1 expression in p53-null cells. Cyclin A1 but not cyclin A2 was upregulated in etoposide-treated tumor cells undergoing p53-dependent apoptosis and mitotic catastrophe. Forced upregulation of cyclin A2 did not induce apoptosis. The data implicate cyclin A1 as a downstream player in p53-dependent apoptosis and G2 arrest.