Aurora-A高表达抑制Cyclin B1泛素化降解诱导其表达上调及在肿瘤发生发展中的作用
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摘要
细胞周期的顺利进行对于维持基因组稳定性至关重要,细胞周期的异常,将导致基因组不稳定性,最终可能导致肿瘤发生。真核细胞的细胞周期受多种调节蛋白调控,这些调节因子的表达和调控异常将导致细胞周期的异常,从而诱发基因组不稳定性和肿瘤形成。Aurora-A和Cyclin B1是两个重要的细胞周期调控蛋白,它们在有丝分裂调控过程中发挥重要作用。Cyclin B1是细胞周期依赖性蛋白激酶CDK1的调节亚基,它通过调节CDK1活性参与有丝分裂调控。Aurora-A是一种中心体相关蛋白激酶,其主要功能是参与中心体成熟和分离、以及双极纺锤体结构的形成。目前已经发现Aurora-A在多种人类肿瘤中存在高表达,Aurora-A高表达诱导细胞出现肿瘤表型,提示Aurora-A可能作为一种潜在的癌基因起作用,但目前关于Aurora-A参与肿瘤发生发展的详细机制尚不清楚。
我们的研究发现,Aurora-A高表达诱导Cyclin B1的表达上调,这种表达上调不是细胞周期分布改变所致;Aurora-A高表达不影响Cyclin B1的转录水平。进一步研究表明,Aurora-A高表达延迟Cyclin B1降解;Aurora-A高表达的细胞中Cyclin B1的泛素化水平降低,Cyclin B1与参与其降解的多种蛋白的结合减弱;Aurora-A和Cyclin B1之间存在体内、体外相互作用。另外,免疫组化分析发现,Aurora-A和Cyclin B1在食管癌中均存在高表达,阳性表达率分别为68.8%和71.7%,更重要的是,Aurora-A和Cyclin B1在食管癌中具有显著的表达相关性。以上结果表明异常高表达的Aurora-A可能通过与Cyclin B1的相互作用抑制其泛素化降解,提高其蛋白稳定性,导致有丝分裂异常、基因组不稳定性,最终导致肿瘤发生发展。
The proper cell cycle progression is essential to maintain the integrity of the genome. The cell cycle of eukaryote is under the accurate control of many cell cycle regulators, whose expression and regulation abnormality has been demonstrated can result in genome instability, the hallmark of many human tumors. Both Aurora-A and Cyclin B1 are the important regulators of the cell cycle. Cyclin B1 is a mitotic Cyclin, which functions mainly at late G2 phase and during mitosis as the regulatory subunit of CDK1. Aurora-A belongs to a multigenic serine/threonine protein kinase family found rescently. Several lines of evidences demonstrate that Aurora-A plays several crucial roles in maturation and separation of centrosome, mitosis spindle assembly and the regulation of cell cycle checkpoints. Aurora-A is amplified and overexpressed in many kinds of human cancers and cancer-derived cell lines, including ESCC (esophageal squamous cell carcinomas), suggesting that when overexpressed, Aurora-A might act as a potential oncogene during tumorigenesis. However, the accurate molecular mechanism by which Aurora-A participates in the development and progression of tumor is unclearly known up to now.
In this paper, we find that when overexpressed, Aurora-A induces up-regulation of Cyclin B1 protein. According to the result of flow cytometry, Aurora-A overexpression has no evident effect on the distribution of cell cycle, which excludes the possibility that the upregulation of Cyclin B1 is due to only the G2/M arrest induced by Aurora-A overexpression. Aurora-A overexpression is not involved in the regulation of Cyclin B1 expression at the transcriptional level. In order to know whether the overexpression of Aurora-A affects the degradation of Cyclin B1, we use the protein stability experiments and find that the degradation of Cyclin B1 is evidently delayed but not blocked in Aurora-A overexpressing ESCC cells compared with that in control cells, which maybe contribute to the increased level of Cyclin B1 protein induced by Aurora-A overexpression. To investigate the molecular mechanism through which overexpressed Aurora-A enhances the protein stability of Cyclin B1, we employed immunoprecipatation experiments. In Aurora-A overexpressing cell line, the level of ubiquitinated-Cyclin B1 is lower than that in control cell line. Furthermore, the interaction of Cyclin B1 with the proteins involving in its ubiquitin-mediated degradation is substantially reduced in Aurora-A overexpressing cells, suggesting that Aurora-A overexpression might inhibite Cyclin B1 to be recognized by and connected to APC/C and its activators. In addition, we find that Aurora-A interacts with Cyclin B1 in vitro and in vivo. Interestingly, immunohistochemistry experiments show that both Aurora-A and Cyclin B1 proteins are overexpressed in human ESCC. Moreover, the deregulated expression of Cyclin B1 is correlated with the overexpression of Aurora-A in ESCC, suggesting a clinical correlation between these two proteins.
Taken together, these findings suggest that overexpression of Aurora-A might upregulate Cyclin B1 protein through inhibiting its ubiquitin-mediated degradation, providing novel insight into understanding the mechanism of how deregulated Aurora-A contributes to genome instability and carcinogenesis.
我们的研究发现,Aurora-A高表达诱导Cyclin B1的表达上调,这种表达上调不是细胞周期分布改变所致;Aurora-A高表达不影响Cyclin B1的转录水平。进一步研究表明,Aurora-A高表达延迟Cyclin B1降解;Aurora-A高表达的细胞中Cyclin B1的泛素化水平降低,Cyclin B1与参与其降解的多种蛋白的结合减弱;Aurora-A和Cyclin B1之间存在体内、体外相互作用。另外,免疫组化分析发现,Aurora-A和Cyclin B1在食管癌中均存在高表达,阳性表达率分别为68.8%和71.7%,更重要的是,Aurora-A和Cyclin B1在食管癌中具有显著的表达相关性。以上结果表明异常高表达的Aurora-A可能通过与Cyclin B1的相互作用抑制其泛素化降解,提高其蛋白稳定性,导致有丝分裂异常、基因组不稳定性,最终导致肿瘤发生发展。
The proper cell cycle progression is essential to maintain the integrity of the genome. The cell cycle of eukaryote is under the accurate control of many cell cycle regulators, whose expression and regulation abnormality has been demonstrated can result in genome instability, the hallmark of many human tumors. Both Aurora-A and Cyclin B1 are the important regulators of the cell cycle. Cyclin B1 is a mitotic Cyclin, which functions mainly at late G2 phase and during mitosis as the regulatory subunit of CDK1. Aurora-A belongs to a multigenic serine/threonine protein kinase family found rescently. Several lines of evidences demonstrate that Aurora-A plays several crucial roles in maturation and separation of centrosome, mitosis spindle assembly and the regulation of cell cycle checkpoints. Aurora-A is amplified and overexpressed in many kinds of human cancers and cancer-derived cell lines, including ESCC (esophageal squamous cell carcinomas), suggesting that when overexpressed, Aurora-A might act as a potential oncogene during tumorigenesis. However, the accurate molecular mechanism by which Aurora-A participates in the development and progression of tumor is unclearly known up to now.
In this paper, we find that when overexpressed, Aurora-A induces up-regulation of Cyclin B1 protein. According to the result of flow cytometry, Aurora-A overexpression has no evident effect on the distribution of cell cycle, which excludes the possibility that the upregulation of Cyclin B1 is due to only the G2/M arrest induced by Aurora-A overexpression. Aurora-A overexpression is not involved in the regulation of Cyclin B1 expression at the transcriptional level. In order to know whether the overexpression of Aurora-A affects the degradation of Cyclin B1, we use the protein stability experiments and find that the degradation of Cyclin B1 is evidently delayed but not blocked in Aurora-A overexpressing ESCC cells compared with that in control cells, which maybe contribute to the increased level of Cyclin B1 protein induced by Aurora-A overexpression. To investigate the molecular mechanism through which overexpressed Aurora-A enhances the protein stability of Cyclin B1, we employed immunoprecipatation experiments. In Aurora-A overexpressing cell line, the level of ubiquitinated-Cyclin B1 is lower than that in control cell line. Furthermore, the interaction of Cyclin B1 with the proteins involving in its ubiquitin-mediated degradation is substantially reduced in Aurora-A overexpressing cells, suggesting that Aurora-A overexpression might inhibite Cyclin B1 to be recognized by and connected to APC/C and its activators. In addition, we find that Aurora-A interacts with Cyclin B1 in vitro and in vivo. Interestingly, immunohistochemistry experiments show that both Aurora-A and Cyclin B1 proteins are overexpressed in human ESCC. Moreover, the deregulated expression of Cyclin B1 is correlated with the overexpression of Aurora-A in ESCC, suggesting a clinical correlation between these two proteins.
Taken together, these findings suggest that overexpression of Aurora-A might upregulate Cyclin B1 protein through inhibiting its ubiquitin-mediated degradation, providing novel insight into understanding the mechanism of how deregulated Aurora-A contributes to genome instability and carcinogenesis.
引文
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