G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv
G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv
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DOI：
10.1038/sj.emboj.7600769
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发表时间：
2005-09-07
期刊：
影响因子：
11.4
通讯作者：
Marine, JC
中科院分区：
文献类型：
--
作者：
Doumont, G;Martoriati, A;Marine, JC
作为对DNA损伤的反应，P53激活G1细胞周期检查点，部分是通过诱导细胞周期蛋白依赖的激酶抑制物p21(Waf1/Cip1)。在这里，我们报告了一个新的直接的p53靶标Ptprv(或ESP)的鉴定，它编码一个跨膜酪氨酸磷酸酶。Ptprv转录在经历P53依赖的细胞周期停滞的培养细胞中显著且优先增加，但在经历P53介导的细胞凋亡的细胞中不明显。这一观察结果在活体中使用Ptprv空报告鼠系得到了进一步证实。Ptprv启动子中存在一个P53反应元件，P53在体内被招募到这个位置。重要的是，虽然在缺乏Ptprv的小鼠中依赖于P53的细胞凋亡是完整的，但在G1检查点控制中，Ptprv缺失的小肠成纤维细胞和上皮细胞是缺陷的。因此，Ptprv是一个新的P53直接靶点，也是P53诱导细胞周期停滞的关键介导物。最后，在接触化学致癌物后，Ptprv的丢失会促进表皮乳头状瘤的形成，这表明Ptprv在体内起到了抑制肿瘤形成的作用。
In response to DNA damage, p53 activates a G1 cell cycle checkpoint, in part through induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Here we report the identification of a new direct p53 target, Ptprv ( or ESP), encoding a transmembrane tyrosine phosphatase. Ptprv transcription is dramatically and preferentially increased in cultured cells undergoing p53-dependent cell cycle arrest, but not in cells undergoing p53-mediated apoptosis. This observation was further confirmed in vivo using a Ptprv null-reporter mouse line. A p53-responsive element is present in the Ptprv promoter and p53 is recruited to this site in vivo. Importantly, while p53-dependent apoptosis is intact in mice lacking Ptprv, Ptprv-null fibroblasts and epithelial cells of the small intestine are defective in G1 checkpoint control. Thus, Ptprv is a new direct p53 target and a key mediator of p53-induced cell cycle arrest. Finally, Ptprv loss enhances the formation of epidermal papillomas after exposure to chemical carcinogens, suggesting that Ptprv acts to suppress tumor formation in vivo.