TRIM25 has a dual function in the p53/Mdm2 circuit
TRIM25 has a dual function in the p53/Mdm2 circuit
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DOI：
10.1038/onc.2015.21
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发表时间：
2015-11-12
期刊：
影响因子：
8
通讯作者：
Blattner, C.
中科院分区：
文献类型：
--
作者：
Zhang, P.;Elabd, S.;Blattner, C.
P53是一种重要的肿瘤抑制因子，在激活时，诱导生长停滞和细胞死亡。因此，p53的控制对于增殖细胞是最重要的，但对于癌症治疗也是如此，其中p53活性有助于根除肿瘤。Mdm2在功能上抑制p53并靶向肿瘤抑制蛋白降解。在遗传筛选中，我们将TRIM 25鉴定为p53和Mdm 2的新型调节剂。TRIM25通过抑制p53和Mdm 2在26 S蛋白酶体中的泛素化和降解来增加它们的丰度。TRIM25与p53和Mdm 2共沉淀，并干扰p300和Mdm 2的结合，这是p53聚泛素化的关键步骤。尽管p53水平增加，但在TRIM 25存在下p53活性被抑制。TRIM25的下调导致HCT 116细胞中p53乙酰化和p53依赖性细胞死亡的增加。在遗传毒性损伤后，TRIM 25抑制了p53依赖性DNA损伤反应。此外，TRIM25的下调导致青鳉早期胚胎发生期间的大量细胞凋亡，这是通过伴随的p53的下调来挽救的，证明了TRIM25在生物体环境中调节p53的功能相关性。
P53 is an important tumor suppressor that, upon activation, induces growth arrest and cell death. Control of p53 is thus of prime importance for proliferating cells, but also for cancer therapy, where p53 activity contributes to the eradication of tumors. Mdm2 functionally inhibits p53 and targets the tumor suppressor protein for degradation. In a genetic screen, we identified TRIM25 as a novel regulator of p53 and Mdm2. TRIM25 increased p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26 S proteasomes. TRIM25 co-precipitated with p53 and Mdm2 and interfered with the association of p300 and Mdm2, a critical step for p53 polyubiquitination. Despite the increase in p53 levels, p53 activity was inhibited in the presence of TRIM25. Downregulation of TRIM25 resulted in an increased acetylation of p53 and p53-dependent cell death in HCT116 cells. Upon genotoxic insults, TRIM25 dampened the p53-dependent DNA damage response. The downregulation of TRIM25 furthermore resulted in massive apoptosis during early embryogenesis of medaka, which was rescued by the concomitant downregulation of p53, demonstrating the functional relevance of the regulation of p53 by TRIM25 in an organismal context.