Effects of oncogenic mutations and DNA response elements on the binding of p53 to p53-binding protein 2 (53BP2)
Effects of oncogenic mutations and DNA response elements on the binding of p53 to p53-binding protein 2 (53BP2)
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DOI：
10.1074/jbc.m604725200
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发表时间：
2006-10-27
影响因子：
4.8
通讯作者：
Fersht, Alan R.
中科院分区：
文献类型：
--
作者：
Tidow, Henning;Veprintsev, Dmitry B.;Fersht, Alan R.
肿瘤抑制因子p53在人类癌症中经常发生突变。一旦激活，它可以诱导细胞周期停滞或凋亡。ASPP 2可以特异性地刺激p53的凋亡功能，但不能刺激细胞周期阻滞，但是促进促凋亡基因的激活超过细胞周期阻滞基因的机制仍然未知。在这项研究中，我们分析了53 BP 2（p53结合蛋白2，C-末端结构域的ASPP 2）的结合p53核心结构域和各种突变体使用生物物理技术。我们发现几个p53核心结构域突变（R181 E、G245 S、R249 S、R273 H）对DNA反应元件和53 BP 2的结合具有不同的影响。此外，我们研究了由53 BP 2，p53和DNA反应元件组成的三元复合物的存在，以深入了解p53的特异性促凋亡激活。我们发现，在GADD 45、p21、Bax和PIG 3的情况下，53 BP 2和DNA与p53的结合是相互排斥的。促凋亡和非凋亡反应元件都被53 BP 2竞争离开p53，没有三元复合物的迹象。
The tumor suppressor p53 is frequently mutated in human cancers. Upon activation it can induce cell cycle arrest or apoptosis. ASPP2 can specifically stimulate the apoptotic function of p53 but not cell cycle arrest, but the mechanism of enhancing the activation of pro-apoptotic genes over cell cycle arrest genes remains unknown. In this study, we analyzed the binding of 53BP2 (p53-binding protein 2, the C-terminal domain of ASPP2) to p53 core domain and various mutants using biophysical techniques. We found that several p53 core domain mutations (R181E, G245S, R249S, R273H) have different effects on the binding of DNA response elements and 53BP2. Further, we investigated the existence of a ternary complex consisting of 53BP2, p53, and DNA response elements to gain insight into the specific pro-apoptotic activation of p53. We found that binding of 53BP2 and DNA to p53 is mutually exclusive in the case of GADD45, p21, Bax, and PIG3. Both pro-apoptotic and non-apoptotic response elements were competed off p53 by 53BP2 with no indication of a ternary complex.