p53 accumulation due to down-regulation of ubiquitin: relevance for neuronal apoptosis.
p53 accumulation due to down-regulation of ubiquitin: relevance for neuronal apoptosis.
复制标题
泛素下调导致 p53 积累：与神经元凋亡的相关性。
DOI：
10.1038/sj.cdd.4400697
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发表时间：
2000
影响因子：
12.4
通讯作者：
Schreiber,SS
中科院分区：
文献类型：
--
作者：
Tan,Z;Qu,W;Tu,W;Liu,W;Baudry,M;Schreiber,SS
p53 肿瘤抑制蛋白是 DNA 损伤后细胞生长停滞和细胞凋亡的主要调节因子。 p53 的功能和稳定性均受到 Mdm2 的严格控制，Mdm2 与 p53 N 末端结合，并以 p53 为目标进行泛素介导的蛋白水解。先前的研究表明，肾上腺切除术诱导的神经元凋亡是p53依赖性的。在这里，我们证明了肾上腺切除大鼠的凋亡海马神经元中 p53 蛋白的核积累和功能激活。尽管 p53 负调节因子 Mdm2 积累并形成 p53-Mdm2 复合物，但 p53 表达仍增加。 p53 表达的持续存在可以通过 p53 阳性神经元中游离泛素的显着减少来解释。将外源泛素添加到来自凋亡神经元的 p53-Mdm2 复合物中可以恢复 p53 的降解。这些发现证明了一种由泛素水平降低介导的 p53 稳定的新机制。因此，调节游离泛素可能是调节某些细胞类型中 p53 依赖性细胞凋亡的有效方法。细胞死亡和分化 (2000) 7, 675–681
The p53 tumor suppressor protein is a major regulator of cell growth arrest and apoptosis in response to DNA damage. Both p53 function and stability are tightly controlled by Mdm2, which binds to the p53 N-terminus and targets p53 for ubiquitin-mediated proteolysis. Previous studies suggest that adrenalectomy-induced neuronal apoptosis is p53-dependent. Here we demonstrate both nuclear accumulation and functional activation of p53 protein in apoptotic hippocampal neurons from adrenalectomized rats. Increased p53 expression occurred despite the accumulation of its negative regulator, Mdm2, and the formation of p53-Mdm2 complexes. The persistence of p53 expression was explained by a striking decrease in free ubiquitin in p53-positive neurons. The addition of exogenous ubiquitin to p53-Mdm2 complexes from apoptotic neurons restored p53 degradation. These findings demonstrate a novel mechanism of p53 stabilization mediated by decreased ubiquitin levels. Regulation of free ubiquitin may therefore be an effective way to modulate p53-dependent apoptosis in certain cell types. Cell Death and Differentiation (2000) 7, 675–681