Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization
Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization
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DOI：
10.1242/jcs.00714
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发表时间：
2003-10-01
影响因子：
4
通讯作者：
Laiho, M
中科院分区：
文献类型：
--
作者：
Kurki, S;Latonen, L;Laiho, M
Mdm2是一种核质和核仁蛋白，与p53和替代阅读框（ARF）肿瘤抑制蛋白相互作用。在这里，我们证明了Mdm2在细胞应激和DNA损伤后与早幼粒细胞白血病（PML）蛋白的重新定位和新的相互作用。我们发现Mdm2和PML在体内和体外通过Mdm2环指结构域和PML c端直接相互作用，Mdm2通过PML的过表达被募集到PML核小体中。紫外线辐射引起的细胞应激和DNA损伤、蛋白酶体和三氧化二砷的下调促进Mdm2和PML损伤特异性核重定位和相互作用以p53不依赖的方式进行。然而，体外分析显示PML、Mdm2和p53形成三聚体复合物。紫外线辐射导致PML核体快速重排，促进PML-p53和PML- mdm2复合物的形成，与p53稳定和p53- mdm2相互作用相一致，表明复合物在时间上是不同的。研究结果表明，Mdm2和PML之间存在新的关联，PML通过与Mdm2的相互作用参与p53的激活和稳定，以应对细胞应激。
Mdm2 is a nucleoplasmic and nucleolar protein interacting with p53 and alternative reading frame (ARF) tumor suppressor proteins. Here we demonstrate relocalization and novel interactions of Mdm2 with the promyelocytic leukemia (PML) protein following cellular stress and DNA damage. We show that Mdm2 and PML interact directly in vivo and in vitro depending on the Mdm2 RING finger domain and the PML C-terminus, and that Mdm2 is recruited to the PML nuclear bodies by overexpression of PML. Cellular stress and DNA damage caused by UV-radiation, downregulation of the proteasome and arsenic trioxide promoted Mdm2 and PML damage-specific nuclear relocalization and interaction in a p53-independent manner. However, in vitro analyses showed that PML, Mdm2 and p53 form trimeric complexes. UV-radiation caused rapid rearrangements of PML nuclear bodies and promoted PML-p53 and PML-Mdm2 complex formation, coinciding with p53 stabilization and preceding p53-Mdm2 interaction suggesting temporally distinct complexes. The results demonstrate novel associations between Mdm2 and PML and show the capacity of PML to participate in the activation and stabilization of p53 in response to cellular stress through PML interaction with Mdm2.