p53 directly suppresses BNIP3 expression to protect against hypoxia-induced cell death
p53 directly suppresses BNIP3 expression to protect against hypoxia-induced cell death
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p53 直接抑制 BNIP3 表达以防止缺氧诱导的细胞死亡
DOI：
10.1038/emboj.2011.248
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发表时间：
2011-08-17
期刊：
影响因子：
11.4
通讯作者：
Xiao, Wuhan
中科院分区：
文献类型：
--
作者：
Feng, Xi;Liu, Xing;Xiao, Wuhan
缺氧稳定肿瘤抑制因子p53，使其主要作为转抑制因子发挥作用；然而，p53在缺氧时的功能尚不清楚。在本研究中，我们发现p53通过直接结合p53应答元件基序并将协同抑制因子mSin3a募集到BNIP3启动子上，从而抑制了BNIP3的表达。p53的dna结合位点必须保持完整，才能抑制BNIP3启动子。此外，我们利用斑马鱼作为体内模型，证实斑马鱼nip3a是哺乳动物niip3的同源基因，确实受到缺氧的诱导，p53突变/敲低下nip3a表达的增强导致p53突变胚胎细胞死亡增强。此外，在人类细胞系和斑马鱼模型中进行的p53敲低/缺失实验表明，p53可以防止由p53抑制BNIP3介导的缺氧诱导的细胞死亡，这与p53的传统促凋亡作用形成了对比。我们的研究结果表明，p53在缺氧诱导的细胞死亡中具有新的功能，从而导致缺血性心脏病和脑中风的新治疗方法的发展。EMBO杂志（2011）30,3397-3415。doi: 10.1038 / emboj.2011.248;2011年7月26日在线发布
Hypoxia stabilizes the tumour suppressor p53, allowing it to function primarily as a transrepressor; however, the function of p53 during hypoxia remains unclear. In this study, we showed that p53 suppressed BNIP3 expression by directly binding to the p53-response element motif and recruiting corepressor mSin3a to the BNIP3 promoter. The DNA-binding site of p53 must remain intact for the protein to suppress the BNIP3 promoter. In addition, taking advantage of zebrafish as an in vivo model, we confirmed that zebrafish nip3a, a homologous gene of mammalian BNIP3, was indeed induced by hypoxia and p53 mutation/knockdown enhanced nip3a expression under hypoxia resulted in cell death enhancement in p53 mutant embryos. Furthermore, p53 protected against hypoxia-induced cell death mediated by p53 suppression of BNIP3 as illustrated by p53 knockdown/loss assays in both human cell lines and zebrafish model, which is in contrast to the traditional pro-apoptotic role of p53. Our results suggest a novel function of p53 in hypoxia-induced cell death, leading to the development of new treatments for ischaemic heart disease and cerebral stoke. The EMBO Journal (2011) 30, 3397-3415. doi:10.1038/emboj.2011.248; Published online 26 July 2011