Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Cell Death Differ. 2013 May;20(5):732-43. doi: 10.1038/cdd.2013.1. Epub 2013 Feb 1.
The transcription factor p53 is a multifunctional tumor suppressor that arrests the cell cycle in response to stress and modulates the DNA repair process or induces apoptosis. The cellular level and activity of p53 are tightly controlled to maintain proper functioning. This study identified a novel p53-binding glycoprotein, gene related to anergy in lymphocytes (Grail), which formed a negative feedback loop (similar to that of Mdm2). Grail physically and functionally interacted with the N-terminus of p53 to target its degradation and modulate its transactivation activity. Grail also senses and regulates cellular p53 levels, modulates a panel of p53-targeted promoters, and has a role in p53-induced apoptosis in cultured cells. Overexpression of Grail inhibited p53-induced apoptosis by increasing p53 degradation. However, cells not expressing Grail failed to undergo p53-dependent apoptosis, resulting in p21-dependent G1 arrest. Thus, Grail may provide a novel regulatory route for controlling p53 activity under stress conditions.
转录因子 p53 是一种多功能肿瘤抑制因子，可响应应激而使细胞周期停滞，并调节 DNA 修复过程或诱导细胞凋亡。p53 的细胞水平和活性受到严格控制，以维持正常功能。本研究鉴定了一种新型的 p53 结合糖蛋白，即与淋巴细胞无反应性相关的基因（Grail），它形成了负反馈环（类似于 Mdm2）。Grail 与 p53 的 N 端物理和功能相互作用，靶向其降解并调节其转录激活活性。Grail 还能感知和调节细胞内的 p53 水平，调节一组 p53 靶向启动子，并在培养细胞中的 p53 诱导凋亡中发挥作用。Grail 的过表达通过增加 p53 降解来抑制 p53 诱导的凋亡。然而，不表达 Grail 的细胞不能进行 p53 依赖性凋亡，导致 p21 依赖性 G1 期阻滞。因此，Grail 可能为应激条件下控制 p53 活性提供了一种新的调节途径。
