E2F-1对c-Myc诱导hTERT表达的负反馈调控作用  

Negative Feedback Regulation of E2F-1 on c-Myc-induced hTERT Expression

作　　者：张安然[1] 张亚飞[1] 章必成[2] 饶智国[2] 高建飞[2] 夏一菊[1] 杨仕明[3] 汪荣泉[1] 房殿春[1] 

机构地区：[1]第三军医大学西南医院消化内科,重庆400038 [2]广州军区武汉总医院肿瘤科 [3]第三军医大学新桥医院消化内科

出　　处：《华南国防医学杂志》2012年第6期527-531,共5页Military Medical Journal of South China

基　　金：国家自然科学基金项目(81101533);中国博士后科学基金项目(20100481468;201104755)

摘　　要：目的探讨转录因子E2F-1(E2F transcription factor 1)对c-Myc诱导端粒酶逆转录酶(human telomerasereverse transcriptase,hTERT)表达的负反馈调控作用。方法以人胚胎成纤维细胞为实验模型,采用基因转染、基因表达抑制实验等探讨E2F-1对c-Myc诱导hTERT表达及下游信号通路的影响。结果 c-Myc激活可同时诱导E2F-1和hTERT的表达,不同的是,仅在c-Myc高度激活时E2F-1表达水平有显著提高,而hTERT表达则呈现一定的剂量依赖性;在c-Myc高度激活时,E2F-1蛋白表达水平显著提高,并致细胞凋亡比率增加;在c-Myc中低度激活时,抑制E2F-1表达,可致hTERT活化水平上升,而在c-Myc高度激活时抑制E2F-1表达,可避免细胞进入凋亡程序,且细胞端粒酶活性有进一步增加。结论在正常细胞中,E2F-1对c-Myc诱导hTERT表达具有负反馈调节作用,对限制癌基因c-Myc的信号转导有重要意义。Objective To investigate the negative feedback regulation of E2F transcription factor 1（E2F-1） on c-Myc-induced hTERT transcription. Methods Human embryonic fibroblast（HEF） cells were used as the model system.The experiments including gene transfection and specific gene expression inhibition,etc.were performed to determine the effects of E2F-1 on c-Myc-induced hTERT transcription and the corresponding downstream signals. Results The increase in c-Myc activity by rAd-c-Myc transfection could enhance expressions of both E2F-1 and hTERT in mRNA and protein level in HEF cells.No dose-dependent effect on E2F-1 expression was observed.In severe c-Myc activation,significant E2F-1 upregulation could be induced,whereas in mild and moderate c-Myc activation,no significant E2F-1 upregulation was found.The increase in hTERT expression level was dose-dependent.In the presence of high levels of c-Myc activation,the expression of E2F-1 protein was increased greatly,which subsequently led to an increased apoptosis rate in HEF cells.In the presence of low/moderate c-Myc activation,inhibition of E2F-1 expression could result in an increase of hTERT expression.In presence of high c-Myc activation,inhibition of E2F-1 expression could restrict cells into apoptosis process and further increase the activity of telomerase. Conclusion In normal cells,E2F-1 exhibits key negative feedback regulation on c-Myc-induced hTERT expression,which is critical to control the transmission of c-Myc-mediated oncogenic signals.

关 键 词：E2F-1 C-MYC 端粒酶逆转录酶 负反馈调控 肿瘤发生 

分 类 号：R730.2[医药卫生—肿瘤]