Mitogen-activated protein kinase phosphatase 2: A novel transcription target of p53 in apoptosis
Mitogen-activated protein kinase phosphatase 2: A novel transcription target of p53 in apoptosis
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DOI：
10.1158/0008-5472.can-05-3878
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Yin, Yuxin
中科院分区：
文献类型：
--
作者：
Shen, Wen Hong;Wang, Jianli;Yin, Yuxin
p53 肿瘤抑制因子通过对其靶基因的转录控制，在细胞周期停滞、衰老和细胞凋亡等多种细胞反应中发挥着关键作用。新 p53 靶基因的鉴定和表征将加深我们对 p53 如何发挥其多种调节功能的理解。在本文中，我们证明丝裂原激活蛋白激酶磷酸酶 2 (MIKP2) 是 p53 介导细胞凋亡的新转录靶标。此外，我们在 MKP2 启动子中鉴定出一个 10 bp 的完美回文基序 (CTGGCGCCAG)，作为 p53 激活 MKP2 基因的新结合位点。这个富含 GC 的回文序列与共有的 p53 结合序列完全不同。 MKP2 的诱导以 p53 依赖性方式对氧化应激高度敏感。有趣的是，p53 依赖性的 MKP2 诱导仅在细胞对导致细胞凋亡的刺激反应中突出，但在细胞周期停滞中并不突出。为了应对氧化应激，MKP2 不仅是 p53 介导的细胞凋亡所必需的，而且异位 MKP2 表达甚至可以独立于 p53 增强细胞凋亡反应。这些数据表明p53通过不同的结合机制调节不同的基因，并且MKP2是p53在细胞凋亡信号传导中的重要靶标。
The p53 tumor suppressor plays critical roles in diverse cellular responses such as cell cycle arrest, senescence, and apoptosis through transcriptional control of its target genes. Identification and characterization of new p53 target genes will advance our understanding of how p53 exerts its multiple regulatory functions. In this article, we show that mitogen-activated protein kinase phosphatase 2 (MIKP2) is a novel transcription target of p53 in mediating apoptosis. Moreover, we identify a 10-bp perfect palindrome motif (CTGGCGCCAG) in the MKP2 promoter as a new binding site for p53 to activate the MKP2 gene. This GC-rich palindrome is completely different from the consensus p53 binding sequence. Induction of MKP2 is highly responsive to oxidative stress in a p53-dependent manner. Interestingly, the p53-dependent induction of MKP2 is prominent only in the cellular response to stimuli leading to apoptosis but not to cell cycle arrest. In response to oxidative stress, MKP2 is not only required for p53-mediated apoptosis, but ectopic MKP2 expression can also enhance apoptotic responses even independent of p53. These data suggest that p53 regulates distinct genes via different binding mechanisms and that MKP2 is an essential target of p53 in signaling apoptosis.