Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells.
Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells.
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DOI：
10.1093/nar/gkt504
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发表时间：
2013-08
影响因子：
14.9
通讯作者：
Resnick MA
中科院分区：
文献类型：
--
作者：
Menendez D;Nguyen TA;Freudenberg JM;Mathew VJ;Anderson CW;Jothi R;Resnick MA
不同的压力对启动子的选择性和肿瘤抑制基因p53的转录调控的影响知之甚少。我们已经采取了全面的方法来表征人类p53网络，包括p53水平，结合，表达和染色质变化在不同的压力。用抗癌药物阿霉素（DXR）或Nutlin-3（Nutlin）处理的人骨肉瘤U2 OS细胞，基于染色质免疫沉淀和高通量测序实验，导致了惊人不同的p53基因结合模式。虽然两个连续的RRCWWGYYY十聚体是共有结合基序，但p53可以结合单个十聚体并在体内发挥功能。尽管Nutlin与p53结合的位点数是DXR的6倍，但与DXR相比，Nutlin诱导的表达变化要小得多。出乎意料的是，溶剂二甲基亚砜（DMSO）单独诱导p53结合到DXR常见的许多位点;然而，这种结合对靶基因表达没有影响。总之，这些数据暗示了p53反式激活的两阶段机制，其中p53结合仅构成第一阶段。此外，p53结合和反式激活与增加的活性组蛋白修饰组蛋白H3赖氨酸4三甲基化。我们发现了149个推定的新p53靶基因，包括几个与肿瘤抑制相关的基因，揭示了癌症治疗的潜在新靶点，并扩大了我们对p53调控网络的理解。
The effects of diverse stresses on promoter selectivity and transcription regulation by the tumor suppressor p53 are poorly understood. We have taken a comprehensive approach to characterizing the human p53 network that includes p53 levels, binding, expression and chromatin changes under diverse stresses. Human osteosarcoma U2OS cells treated with anti-cancer drugs Doxorubicin (DXR) or Nutlin-3 (Nutlin) led to strikingly different p53 gene binding patterns based on chromatin immunoprecipitation with high-throughput sequencing experiments. Although two contiguous RRRCWWGYYY decamers is the consensus binding motif, p53 can bind a single decamer and function in vivo. Although the number of sites bound by p53 was six times greater for Nutlin than DXR, expression changes induced by Nutlin were much less dramatic compared with DXR. Unexpectedly, the solvent dimethylsulphoxide (DMSO) alone induced p53 binding to many sites common to DXR; however, this binding had no effect on target gene expression. Together, these data imply a two-stage mechanism for p53 transactivation where p53 binding only constitutes the first stage. Furthermore, both p53 binding and transactivation were associated with increased active histone modification histone H3 lysine 4 trimethylation. We discovered 149 putative new p53 target genes including several that are relevant to tumor suppression, revealing potential new targets for cancer therapy and expanding our understanding of the p53 regulatory network.
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影响因子：
3.9
作者：
Chang, ZeNan;Guo, Chin-Lin;Ahronowitz, Iris;Stemmer-Rachamimov, Anat O.;MacCollin, Mia;Nunes, Fabio P.
通讯作者：
Nunes, Fabio P.
影响因子：
4.5
作者：
Jordan JJ;Menendez D;Inga A;Noureddine M;Bell DA;Resnick MA
通讯作者：
Resnick MA
影响因子：
14.9
作者：
Jothi, Raja;Cuddapah, Suresh;Barski, Artem;Cui, Kairong;Zhao, Keji
通讯作者：
Zhao, Keji
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA
影响因子：
5.3
作者：
FUNK, WD;PAK, DT;SHAY, JW
通讯作者：
SHAY, JW