p53对乳腺癌耐药蛋白基因的转录调控  

Transcriptional Regulation of Breast Cancer Resistance Protein(BCRP) by p53 in p53-null Saos-2 cells

作　　者：吴新刚[1] 彭姝彬[1] 闾四平[1] 张年凤[1] 邹进[1] 

机构地区：[1]岳阳职业技术学院医学基础部,湖南岳阳414000

出　　处：《中国生物化学与分子生物学报》2012年第2期152-157,共6页Chinese Journal of Biochemistry and Molecular Biology

基　　金：岳阳职业技术学院项目资助(No.YZ1104G)~~

摘　　要：乳腺癌耐药蛋白(breast cancer resistance protein,BCRP)是ATP结合盒转运蛋白超家族成员之一,其通过主动外排化疗药物如米托蒽醌、托泊替康和甲氨蝶呤,进而介导肿瘤化疗耐受.最近有研究发现,在野生型p53(wild type p53,wt-p53)低表达的乳腺癌细胞系MCF-7中,外源性wt-p53通过抑制核转录因子-κB(nuclear factor-κB,NF-κB)的活性进而抑制BCRP的表达,但其详细的分子机制有待进一步阐明.本研究选用p53缺失的骨肉瘤细胞系Saos-2,通过瞬时转染技术发现,wt-p53可以激活BCRP的表达,而突变型p53的激活作用消失;报告基因试验显示,wt-p53可以上调BCRP启动子活性;通过生物信息学软件MatInspector对BCRP启动子区进行预测,未发现p53结合元件;同时,通过转染IκB抑制Saos-2细胞中NF-κB的活性后发现,Saos-2细胞中NF-κB活性越低,p53对BCRP启动子的激活作用越弱甚至完全消失.上述结果提示,p53对Saos-2细胞中BCRP的激活作用是NF-κB依赖性的.Breast cancer resistance protein（BCRP） is a member of the ATP-binding cassette（ABC） transporter superfamily.BCRP confers drug resistance in cancer by transporting chemotherapeutic agents such as mitoxantrone,topotecan,and methotrexate.Although a recent study demonstrated that wild type p53（wt-p53） may suppress BCRP expression through the nuclear factor-κB（NF-κB） pathway in breast cancer cell line MCF-7,which expresses wt-p53 at low level,the detailed molecular mechanisms of transcriptional regulation on BCRP remain unclear.Here,we set out to reveal the exogenous p53＇s role on the expression of BCRP.In the human osteosarcoma cell line Saos-2,a p53-null cell line,transient transfection assays showed that the BCRP expression was activated by wt-p53 but not p53 mutants,p53R175H and p53R248W.We further co-transfected the p53 expression plasmid with BCRP luciferase promoter reporter construct into the Saos-2 cell,and the results revealed that wt-p53 may facilitate the BCRP promoter activity.However,we did not find any p53 binding site by applying MatInspector.Strikingly,NF-κB activity inhibition downplayed the activation effect of BCRP promoter activity by wt-p53.These results suggested that transcriptional activation of BCRP by wt-p53 is NF-κB-dependent.

关 键 词：乳腺癌耐药蛋白 P53 核转录因子-ΚB 

分 类 号：R730[医药卫生—肿瘤] Q753[医药卫生—临床医学]