Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences
Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences
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DOI：
10.1073/pnas.0909129107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Resnick, Michael A.
中科院分区：
文献类型：
--
作者：
Menendez, Daniel;Inga, Alberto;Resnick, Michael A.
P53是一个主要的调控，序列特异性转录因子，直接控制100多个基因的表达，以响应各种应激信号。通常认为，通过p53与由两个5‘-RRRCWWGYYY-3’十轴组成的共识反应元件（RE）结合，发生反活化。最近，通过对人血管生成相关基因FLT1的研究，我们发现p53可以在非典型1/2位点介导有限的转激活，并可以与雌激素受体（ER）在邻近ER 1/2位点顺式协同作用。为了解决p53和ER协同反激活的普遍性，FLT1启动子中的1/2位点被替换为各种1/2位点，以及人类靶基因的典型弱和强p53 REs。配体激活的ER顺式作用大大增强了所有测试序列的p53反激活。此外，增强的反活化延伸到几种功能改变的癌症相关p53突变体，这表明至少在一些res中，er依赖性突变体p53具有活性。p63和p73也发现了增强的反活化。我们提出p53家族和内质网主调控因子在p53靶正则和非正则REs的转激活中存在一般的协同关系，这些正则和非正则REs本身可能对p53反应不佳。这种关系在受影响的基因和表达水平方面极大地扩展了p53调控的转录主网络，并对癌症的出现和可能的治疗具有启示意义。
p53 is a master regulatory, sequence-specific transcription factor that directly controls expression of over 100 genes in response to various stress signals. Transactivation is generally considered to occur through p53 binding to a consensus response element (RE) composed of two 5'-RRRCWWGYYY-3' decamers. Recently, studying the human angiogenesis-related gene FLT1 we discovered that p53 can mediate limited transactivation at a noncanonical 1/2 site and could synergize with the estrogen receptor (ER) acting in cis at a nearby ER 1/2 site. To address the generality of concerted transactivation by p53 and ER, the 1/2 site in the FLT1 promoter was replaced with a variety of 1/2 sites, as well as canonical weak and strong p53 REs of human target genes. The p53 transactivation of all tested sequences was greatly enhanced by ligand-activated ER acting in cis. Furthermore, enhanced transactivation extends to several cancer-associated p53 mutants with altered function, suggesting ER-dependent mutant p53 activity for at least some REs. The enhanced transactivation was also found with p63 and p73. We propose a general synergistic relationship between p53 family and ER master regulators in transactivation of p53 target canonical and noncanonical REs, which might be poorly responsive to p53 on their own. This relationship greatly expands the transcriptional master network regulated by p53 in terms of genes affected and levels of expression and has implications for the appearance and possible treatments of cancer.