摘要
p16~(INK4a)基因编码细胞周期蛋白依赖激酶的抑制因子,p16~(INK4a)蛋白通过负调控CDK4/6的活性在细胞周期进行及细胞分化过程中发挥作用,因而p16~(INK4a)基因的表达调控一直受到广泛的关注。很多证据表明,p16~(INK4a)的表达受表观遗传修饰的调控并且与多种肿瘤的发生密切相关。尽管近来生化方面的研究表明表观遗传修饰,例如DNA甲基化和组蛋白修饰,参与了p16~(INK4a)基因的表达调控,但是目前还没有关于组蛋白乙酰化修饰对p16~(INK4a)基因表达调控机制的详细报道。在本文中,我们对组蛋白乙酰转移酶p300通过上调p16~(INK4a)的表达而抑制HeLa细胞周期的进程及其可能的机制进行了深入的研究。我们的工作证实过量表达p300能抑制细胞周期的进行,而这一过程可通过small interfering RNA (siRNA)降低p16~(INK4a)蛋白的水平而被逆转。在293T细胞中,p300参与p16~(INK4a)的表达调控,而且p300和Sp1对p16~(INK4a)启动子水平,mRNA水平及蛋白水平的调控作用具有协同效果。针对Sp1和p300设计的siRNA能够通过部分地抑制Sp1和p300的表达而抑制p16~(INK4a)启动子的活性。免疫共沉淀(CoIP)和哺乳动物双杂交实验表明,Sp1和p300通过Sp1的N末端和p300的Q区的相互作用而存在于同一复合物中。p16~(INK4a)启动子截短突变和点突变报告基因荧光素酶活性分析表明在p300和Sp1调控p16~(INK4a)启动子活性过程中p16~(INK4a)启动子近端的Sp1结合位点起重要作用。染色质免疫沉淀(ChIP)实验证实,p300通过Sp1招募到p16~(INK4a)启动子区域;p300固有的乙酰转移酶活性在p300参与p16~(INK4a)的表达调控中是必需的;p300通过增强p16~(INK4a)启动子区域的组蛋白H4的乙酰化水平促进p16~(INK4a)基因的启动子活性。我们的研究工作将有助于更好的阐述p16~(INK4a)基因转录调控的特异机制,并为基于p16~(INK4a)的基因治疗提供重要的理论基础。
The regulation of expression of p16~(INK4a) gene has attracted a great deal of research attention, because this gene encodes a cyclin-dependent kinase inhibitor that plays a key role in cell cycle progression and cellular differentiation by negatively regulating the CDK4/6 activity. There has been increasing evidence that the expression of p16~(INK4a) gene is epigenetically controlled and is closely related with many cancers. Although previous biochemical studies revealed that epigenetic mechanisms such as DNA methylation and histone modifications may be involved in transcription regulation of this gene, a detailed description of the molecular basis for the roles of histone acetylation in p16~(INK4a) regulation has not been reported. In this study, we demonstrate that p300 was able to induce cell cycle arrest, and this process was reversed by p16~(INK4a) silencing by small interference RNA (siRNA) in HeLa cells. We also showed that p300 was involved in activation of p16~(INK4a) expression in 293T cells. Specifically, p300 cooperated with Sp1 to stimulate both the p16~(INK4a) promoter activity and the mRNA expression. The siRNA-induced partial silencing of Sp1 and p300 resulted in a significant inhibition of the p16~(INK4a) promoter activity. Co-immunoprecipitation (CoIP) and mammalian two-hybrid assays revealed that p300 and Sp1 formed a complex through interaction between the Q domain of p300 and the N-terminal domain of Sp1. The results of p16~(INK4a) promoter truncation mutants and point mutations linked to a luciferase reporter gene assays indicated that the proximal Sp1-binding site of p16~(INK4a) promoter played very important roles in its transcription activation by p300 and Sp1. The chromatin immunoprecipitation (ChIP) assays verified that p300 was recruited to p16~(INK4a) promoter, and the intrinsic histone acetyltransferase (HAT) activity of p300 was essential for p16~(INK4a) promoter activation through inducing the hyperacetylation of histone H4 at the p16~(INK4a) gene. These data will contribute to elucidating the unique mechanisms of p16~(INK4a) transcriptional control, which is crucial to the development of new therapeutic strategies for p16~(INK4a) -related gene therapy.
引文
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