p53 regulates the transcription of its Δ133p53 isoform through specific response elements contained within the TP53 P2 internal promoter
p53 regulates the transcription of its Δ133p53 isoform through specific response elements contained within the TP53 P2 internal promoter
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DOI：
10.1038/onc.2010.26
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发表时间：
2010-05-06
期刊：
影响因子：
8
通讯作者：
Hainaut, P.
中科院分区：
文献类型：
--
作者：
Marcel, V.;Vijayakumar, V.;Hainaut, P.
抑癌基因P53蛋白被基因毒性应激激活，调控衰老、细胞凋亡和细胞周期停滞相关基因。已经描述了九种P53亚型，它们可能调节规范的P53蛋白的抑制功能。其中，Delta 133P53缺乏132个近端残基，已被证明可调节P53诱导的细胞凋亡和细胞周期停滞。Delta 133P53是由位于TP53基因内含子1和外显子5之间的另一个启动子P2驱动的一种特定的mRNA p53I4表达的。在这里，我们报告P2启动子是以P53依赖的方式调节的。在野生型P53细胞系中，Delta133P53的表达随着阿霉素的DNA损伤而增加，但在突变型P53细胞中不表达。染色质免疫沉淀和使用P2启动子缺失构建的荧光素酶分析表明，P53结合位于P2启动子内的功能反应元件。我们还发现Delta 133P53在体外并不与P53共识DNA序列特异性结合，但在特异性DNA结合分析中与野生型P53竞争。最后，我们报道了Delta 133P53在克隆形成实验中抵消了P53依赖的生长抑制。这些观察结果表明，D133p53是P53的一个新靶点，它可能参与了控制P53功能的负反馈环。Oncogene(2010)29,2691-2700；doi：10.1038/onc.2010.26；2010年3月1日在线发布
The tumor suppressor p53 protein is activated by genotoxic stress and regulates genes involved in senescence, apoptosis and cell-cycle arrest. Nine p53 isoforms have been described that may modulate suppressive functions of the canonical p53 protein. Among them, Delta 133p53 lacks the 132 proximal residues and has been shown to modulate p53-induced apoptosis and cell-cycle arrest. Delta 133p53 is expressed from a specific mRNA, p53I4, driven by an alternative promoter P2 located between intron 1 and exon 5 of TP53 gene. Here, we report that the P2 promoter is regulated in a p53-dependent manner. Delta 133p53 expression is increased in response to DNA damage by doxorubicin in p53 wild-type cell lines, but not in p53-mutated cells. Chromatin immunoprecipitation and luciferase assays using P2 promoter deletion constructs indicate that p53 binds functional response elements located within the P2 promoter. We also show that Delta 133p53 does not bind specifically to p53 consensus DNA sequence in vitro, but competes with wild-type p53 in specific DNA-binding assays. Finally, we report that Delta 133p53 counteracts p53-dependent growth suppression in clonogenic assays. These observations indicate that D133p53 is a novel target of p53 that may participate in a negative feedback loop controlling p53 function. Oncogene (2010) 29, 2691-2700; doi:10.1038/onc.2010.26; published online 1 March 2010