Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
Cell Death Differ. 2012 Dec;19(12):1992-2002. doi: 10.1038/cdd.2012.89. Epub 2012 Jul 13.
The tumor-suppressor p53 can induce various biological responses. Yet, it is not clear whether it is p53 in vivo promoter selectivity that triggers different transcription programs leading to different outcomes. Our analysis of genome-wide chromatin occupancy by p53 using chromatin immunoprecipitation (ChIP)-seq revealed 'p53 default program', that is, the pattern of major p53-bound sites that is similar upon p53 activation by nutlin3a, reactivation of p53 and induction of tumor cell apoptosis (RITA) or 5-fluorouracil in breast cancer cells, despite different biological outcomes. Parallel analysis of gene expression allowed identification of 280 novel p53 target genes, including p53-repressed AURKA. We identified Sp1 as one of the p53 modulators, which confer specificity to p53-mediated transcriptional response upon RITA. Further, we found that STAT3 antagonizes p53-mediated repression of a subset of genes, including AURKA.
肿瘤抑制因子 p53 可以诱导各种生物反应。然而，目前尚不清楚是否是 p53 体内启动子的选择性触发了不同的转录程序，从而导致不同的结果。我们使用染色质免疫沉淀（ChIP）-seq 分析了全基因组范围内 p53 的染色质占有率，发现了“p53 默认程序”，即在乳腺癌细胞中，nutlin3a 激活 p53、重新激活 p53 和诱导肿瘤细胞凋亡（RITA）或 5-氟尿嘧啶时，p53 结合位点的主要模式相似，尽管生物学结果不同。平行的基因表达分析确定了 280 个新的 p53 靶基因，包括 p53 抑制的 AURKA。我们确定 Sp1 是 p53 调节剂之一，它在 RITA 时赋予 p53 介导的转录反应特异性。此外，我们发现 STAT3 拮抗 p53 对包括 AURKA 在内的一组基因的抑制。
