Dmp1 physically interacts with p53 and positively regulates p53's stability, nuclear localization, and function.
Dmp1 physically interacts with p53 and positively regulates p53's stability, nuclear localization, and function.
复制标题
DOI：
10.1158/0008-5472.can-11-2410
复制
发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Inoue K
中科院分区：
文献类型：
--
作者：
Frazier DP;Kendig RD;Kai F;Maglic D;Sugiyama T;Morgan RL;Fry EA;Lagedrost SJ;Sui G;Inoue K
转录因子Dmp 1是Ras/HER 2激活的单倍不足肿瘤抑制因子，其激活细胞周期停滞的Arf/p53途径。最近的证据表明，在某些细胞类型中，Dmp 1可以独立于Arf激活p53。在这里，我们报告的结果支持这一概念的定义Arf独立功能的Dmp 1在肿瘤抑制。我们发现Dmp 1和p53可以通过p53的羧基端和Dmp 1的DNA结合结构域在哺乳动物细胞中直接相互作用。Dmp 1的表达拮抗了Mdm 2对p53的泛素化，并促进了p53的核定位。Dmp 1-p53结合显著增加p53的水平，独立于Dmp 1的DNA结合活性。从机制上讲，p53靶基因通过在p53−/−; Arf−/−细胞中共表达Dmp 1和p53而协同激活，这些基因的遗传毒性反应在Dmp 1 −/−和p53−/−细胞中比在Arf−/−细胞中受到更大的阻碍。总之，我们的研究结果确定了一个强大的新机制，通过Dmp 1和p53之间的直接物理相互作用介导的p53激活。
The transcription factor Dmp1 is a Ras/HER2-activated haplo-insufficient tumor suppressor that activates the Arf/p53 pathway of cell cycle arrest. Recent evidence suggests that Dmp1 may activate p53 independently of Arf in certain cell types. Here we report findings supporting this concept with the definition an Arf-independent function for Dmp1 in tumor suppression. We found that Dmp1 and p53 can interact directly in mammalian cells via the carboxyl-terminus of p53 and the DNA-binding domain of Dmp1. Expression of Dmp1 antagonized ubiquitination of p53 by Mdm2 and promoted nuclear localization of p53. Dmp1-p53 binding significantly increased the level of p53, independent of Dmp1’s DNA-binding activity. Mechanistically, p53 target genes were activated synergistically by co-expression of Dmp1 and p53 in p53−/−; Arf−/−cells and genotoxic responses of these genes were hampered more dramatically in Dmp1−/− and p53−/− cells than in Arf−/− cells. Together, our findings identify a robust new mechanism of p53 activation mediated through by direct physical interaction between Dmp1 and p53.