Tong Y, Tan Y, Zhou C, Melmed S
Department of Medicine, Cedars-Sinai Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Oncogene. 2007 Aug 16;26(38):5596-605. doi: 10.1038/sj.onc.1210339. Epub 2007 Mar 12.
Pituitary tumor transforming gene (PTTG1) was isolated from rat pituitary tumor cells, and subsequently identified as a securin protein as well as a transcription factor. We show here a global transcriptional effect of PTTG1 in human choriocarcinoma JEG-3 cells by simultaneously assessing 20,000 gene promoters using chromatin immunoprecipitation (ChIP)-on-Chip experiments. Seven hundred and forty-six gene promoters (P<0.001) were found enriched, with functions relating to cell cycle, metabolic control and signal transduction. Significant interaction between PTTG1 and Sp1 (P<0.000001) was found by transcriptional pattern analysis of ChIP data and further confirmed by immunoprecipitation and pull-down assays. PTTG1 acts coordinately with Sp1 to induce cyclin D3 expression approximately threefold, and promotes G1/S-phase transition independently of p21. PTTG1 deletion was also protective for anchorage-independent cell colony formation. The results show that PTTG1 exhibits properties of a global transcription factor, and specifically modulates the G1/S-phase transition by interacting with Sp1. This novel signaling pathway may be required for PTTG1 transforming activity.
垂体肿瘤转化基因（PTTG1）是从大鼠垂体肿瘤细胞中分离出来的，随后被鉴定为一种分离酶蛋白以及一种转录因子。我们在此通过染色质免疫沉淀（ChIP）芯片实验同时评估20,000个基因启动子，展示了PTTG1在人绒毛膜癌JEG - 3细胞中的全局转录效应。发现746个基因启动子（P<0.001）富集，其功能与细胞周期、代谢控制和信号转导有关。通过对ChIP数据的转录模式分析发现PTTG1与Sp1之间存在显著相互作用（P<0.000001），并通过免疫沉淀和下拉实验进一步证实。PTTG1与Sp1协同作用，使细胞周期蛋白D3表达增加约三倍，并独立于p21促进G1/S期转变。PTTG1缺失对非锚定依赖性细胞集落形成也有保护作用。结果表明，PTTG1具有全局转录因子的特性，并通过与Sp1相互作用特异性地调节G1/S期转变。这种新的信号通路可能是PTTG1转化活性所必需的。
