E2F1 induces pituitary tumor transforming gene (PTTG1) expression in human pituitary tumors.
E2F1 induces pituitary tumor transforming gene (PTTG1) expression in human pituitary tumors.
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DOI：
10.1210/me.2009-0161
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发表时间：
2009-12
影响因子：
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通讯作者：
Cuiqi Zhou;K. Wawrowsky;S. Bannykh;S. Gutman;S. Melmed
中科院分区：
文献类型：
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作者：
Cuiqi Zhou;K. Wawrowsky;S. Bannykh;S. Gutman;S. Melmed
Rb/E2 F在小鼠和人垂体瘤中失调。垂体瘤转化基因（PTTG 1）是一种securin蛋白，是垂体瘤发生所必需的，PTTG 1缺失可减弱Rb（+/-）小鼠垂体瘤的发生。E2 F1和PTTG 1在46例Rb（+/-）小鼠垂体组织中有29例呈一致性过表达，在80例人垂体瘤中有45例呈一致性过表达（P < 0.05）。通过染色质免疫沉淀和生物素-链霉亲和素下拉试验评估，E2 F1特异性结合hPTTG 1启动子，表明hPTTG 1可能作为直接E2 F1靶点。转染E2 F1及其伴侣DP 1剂量依赖性地激活hPTTG 1转录高达3倍，在p53缺失的H1299细胞中，但在p53充满的HCT 116细胞中没有。E2 F1过表达可使H1299细胞内源性hPTTG 1 mRNA和蛋白水平提高3倍。内源性p53/p21的存在限制了诱导，而在HCT 116细胞中敲低p53或p21恢复E2 F1诱导的hPTTG 1反式激活和表达。此外，通过小干扰RNA抑制Rb一致地升高E2 F1和hPTTG 1蛋白水平。相反，转染E2 F1小干扰RNA降低hPTTG 1水平24小时后，在HCT 116比在H1299细胞，表明p53延迟E2 F1对hPTTG 1的作用。这些结果阐明了丰富的肿瘤hPTTG 1表达的机制，从而Rb失活释放E2 F1诱导hPTTG 1。该信号通路可能是垂体肿瘤发生需要PTTG 1的基础。
Rb/E2F is dysregulated in murine and human pituitary tumors. Pituitary tumor transforming gene (PTTG1), a securin protein, is required for pituitary tumorigenesis, and PTTG1 deletion attenuates pituitary tumor development in Rb(+/-) mice. E2F1 and PTTG1 were concordantly overexpressed in 29 of 46 Rb(+/-) murine pituitary tissues and also in 45 of 80 human pituitary tumors (P < 0.05). E2F1 specifically bound the hPTTG1 promoter as assessed by chromatin immunoprecipitation and biotin-streptavidin pull-down assay, indicating that hPTTG1 may act as a direct E2F1 target. Transfection of E2F1 and its partner DP1 dose-dependently activated hPTTG1 transcription up to 3-fold in p53-devoid H1299 cells but not in p53-replete HCT116 cells. E2F1 overexpression enhanced endogenous hPTTG1 mRNA and protein levels up to 3-fold in H1299 cells. The presence of endogenous p53/p21 constrained the induction, whereas knocking down either p53 or p21 in HCT116 cells restored E2F1-induced hPTTG1 transactivation and expression. Moreover, suppressing Rb by small interfering RNA concordantly elevated E2F1 and hPTTG1 protein levels. In contrast, transfection of E2F1 small interfering RNA lowered hPTTG1 levels 24 h later in HCT116 than in H1299 cells, indicating that p53 delays E2F1 action on hPTTG1. These results elucidate a mechanism for abundant tumor hPTTG1 expression, whereby Rb inactivation releases E2F1 to induce hPTTG1. This signaling pathway may underlie the requirement of PTTG1 for pituitary tumorigenesis.