Tumor Protein 53-Induced Nucear Protein 1 Is a Major Mediator of p53 Antioxidant Function
Tumor Protein 53-Induced Nucear Protein 1 Is a Major Mediator of p53 Antioxidant Function
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DOI：
10.1158/0008-5472.can-08-2320
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发表时间：
2009-01-01
期刊：
影响因子：
11.2
通讯作者：
Carrier, Alice
中科院分区：
文献类型：
--
作者：
Cano, Carla E.;Gommeaux, Julien;Carrier, Alice
p53主要通过转录诱导参与细胞周期检查点、细胞凋亡和调节细胞氧化还原状态等过程的靶基因发挥其肿瘤抑制功能。p53抗氧化功能依赖于其转录活性，并通过抗氧化和促凋亡靶点的顺序诱导而进行。然而，迄今为止，没有一个著名的p53靶点被证明能够消除由p53缺乏引起的细胞内活性氧（ROS）积累，因此指出存在其他突出但未知的p53抗氧化剂靶点。在这里，我们表明TP53INP1代表这样的目标。事实上，TP53INP1转录诱导氧化应激是严格依赖于p53。来自TP53 INP1缺陷（inp1（-/-））小鼠的小鼠胚胎成纤维细胞（MEF）抗脾细胞积累细胞内ROS，而在p53缺陷的MEF中TP53 INP1的过表达将ROS水平拯救到p53-熟练细胞的ROS水平，表明TP53 INP1抗氧化剂功能是1353独立的。此外，氧化剂刺激时inp（-1-）细胞中ROS的积累与p53靶点p21/Cdkn1a、Sesn 2、TAp73、Puma和Bax的表达降低相关。p53 Ser（58）（相当于人p53 Ser（46））的突变消除了这些基因的转录，表明TP53 INP1介导的p53 Ser 58磷酸化参与了这一过程。此外，TP53 INP1缺乏导致抗氧化剂（N-乙酰半胱氨酸）敏感的细胞增殖加速。最后，TP53INP1缺陷增加了氧化应激相关淋巴瘤的发病率，并降低了P53（+/-）小鼠的存活率。总之，我们的数据表明TP 53 INP 1是p53驱动的氧化应激反应的主要作用者，具有p53非依赖性细胞内活性氧调节功能和p53依赖性转录调节功能。[Cancer Res 2009; 69（l）：219 - 26]
p53 exerts its tumor suppressor function mainly through transcriptional induction of target genes involved in several processes, including cell cycle checkpoints, apoptosis, and regulation of cell redox status. p53 antioxidant function is dependent on its transcriptional activity and proceeds by sequential induction of antioxidant and proapoptotic targets. However, none of the thus far renowned p53 targets have proved able to abolish on their own the intracellular reactive oxygen species (ROS) accumulation caused by p53 deficiency, therefore pointing to the existence of other prominent and yet unknown p53 antioxidant targets. Here, we show that TP53INP1 represents such a target. Indeed, TP53INP1 transcript induction on oxidative stress is strictly dependent on p53. Mouse embryonic fibroblasts (MEF) anti splenocytes derived from TP53INP1-deficient (inp1(-/-)) mice accumulate intracellular ROS, whereas overexpression of TP53INP1 in p53-deficient MEFs rescues ROS levels to those of p53-proficient cells, indicating that TP53INP1 antioxidant, function is 1353 independent. Furthermore, accumulation of ROS in inp(-1-) cells on oxidant challenge is associated with decreased expression of p53 targets p21/Cdkn1a, Sesn2, TAp73, Puma, and Bax. Mutation of p53 Ser(58) (equivalent to human p53 Ser(46)) abrogates transcription of these genes, indicating that TP53INP1-mediated p53 Ser58 phosphorylation is implicated in this process. In addition, TP53INP1 deficiency results in an antioxidant (N-acetyleysteine)-sensitive acceleration of cell proliferation. Finally, TP53INP1 deficiency increases oxidative stress-related lymphoma incidence and decreases survival of P53(+/-) mice. In conclusion, our data show that TP53INP1 is it major actor of p53-driven oxidative stress response that possesses both a p53-independent intracellular ROS regulatory function and a p53-dependent, transcription regulatory function. [Cancer Res 2009;69(l):219-26]