Di Agostino Silvia, Strano Sabrina, Emiliozzi Velia, Zerbini Valentina, Mottolese Marcella, Sacchi Ada, Blandino Giovanni, Piaggio Giulia
Experimental Oncology Department, Istituto Regina Elena, Via delle Messi D'Oro 156, 00158 Rome, Italy.
Cancer Cell. 2006 Sep;10(3):191-202. doi: 10.1016/j.ccr.2006.08.013.
This article investigates the mechanistic aspects of mutant p53 "gain of function" in response to DNA damage. We show that mutant forms of p53 protein interact with NF-Y. The expression of cyclin A, cyclin B1, cdk1, and cdc25C, as well as the cdk1-associated kinase activities, is upregulated after DNA damage, provoking a mutant p53/NF-Y-dependent increase in DNA synthesis. Mutant p53 binds NF-Y target promoters and, upon DNA damage, recruits p300, leading to histone acetylation. The recruitment of mutant p53 to the CCAAT sites is severely impaired upon abrogation of NF-YA expression. Endogenous NF-Y, mutant p53, and p300 proteins form a triple complex upon DNA damage. We demonstrate that aberrant transcriptional regulation underlies the ability of mutant p53 proteins to act as oncogenic factors.
本文研究了突变型p53“功能获得”在响应DNA损伤时的机制方面。我们发现p53蛋白的突变形式与NF-Y相互作用。DNA损伤后，细胞周期蛋白A、细胞周期蛋白B1、细胞周期蛋白依赖性激酶1（cdk1）和细胞周期蛋白磷酸酶25C（cdc25C）的表达以及与cdk1相关的激酶活性上调，引发了依赖于突变型p53/NF-Y的DNA合成增加。突变型p53结合NF-Y靶启动子，并在DNA损伤时募集p300，导致组蛋白乙酰化。当NF-YA表达被消除时，突变型p53向CCAAT位点的募集严重受损。内源性NF-Y、突变型p53和p300蛋白在DNA损伤时形成三聚体复合物。我们证明异常的转录调控是突变型p53蛋白作为致癌因子发挥作用的基础。
