New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53
New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53
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DOI：
10.1038/onc.2008.409
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发表时间：
2009-01-29
期刊：
影响因子：
8
通讯作者：
Yoo, O-J
中科院分区：
文献类型：
--
作者：
Min, S-H;Kim, D. M.;Yoo, O-J
除了MDM 2、COP 1和PIRH 2外，大多数p53靶基因在凋亡、分化和细胞周期阻滞中发挥作用。上述癌基因通过负反馈机制下调p53，从而有助于肿瘤的发展。在这项研究中，我们报告了一种新的p53靶点PRL-1，它被认为是多种癌症类型发展和转移的重要调节因子。再生肝磷酸酶1（PRL-1）过表达降低内源性和外源性p53蛋白的水平，并抑制p53介导的细胞凋亡。另一方面，通过小干扰RNA（siRNA）切除PRL-1增加了p53蛋白水平。p53的下调是由p53泛素化和随后的蛋白酶体降解介导的。此外，PRL-1通过两个独立的途径实现p53泛素化，即通过诱导PIRH 2转录和通过Akt信号转导诱导MDM 2磷酸化。此外，我们发现PRL-1基因在第一内含子中含有一个p53反应元件，其转录受p53蛋白的调控。这些发现意味着新的致癌p53靶点PRL-1可能通过负反馈机制下调p53而促进肿瘤的发展。
Most of the p53 target genes, all except MDM2, COP1 and PIRH2, perform functions in apoptosis, differentiation and cell cycle arrest. The aforementioned oncogenes downregulate p53 through a negative feedback mechanism, and thus contribute to tumor development. In this study, we report a new p53 target, PRL-1, which is believed to be a significant regulator in the development and metastasis of a variety of cancer types. Phosphatase of regenerating liver 1 (PRL-1) overexpression reduced the levels of endogenous and exogenous p53 proteins, and inhibited p53-mediated apoptosis. On the other hand, the ablation of PRL-1 by small interfering RNA (siRNA) increased p53 protein levels. The p53 downregulation was mediated by p53 ubiquitination and subsequent proteasomal degradation. Furthermore, p53 ubiquitination by PRL-1 was achieved through two independent pathways, by inducing PIRH2 transcription and by inducing MDM2 phosphorylation through Akt signaling. In addition, we showed that the PRL-1 gene harbors a p53 response element in the first intron, and its transcription is regulated by the p53 protein. These findings imply that the new oncogenic p53 target, PRL-1, may contribute to tumor development by the downregulation of p53 by a negative feedback mechanism.