Kitamura Y, Ota T, Matsuoka Y, Tooyama I, Kimura H, Shimohama S, Nomura Y, Gebicke-Haerter P J, Taniguchi T
Department of Neurobiology, Kyoto Pharmaceutical University, Japan.
Glia. 1999 Jan 15;25(2):154-64.
It is now generally accepted that massive neuronal death due to oxidative stress is a regular feature of brains in neurodegenerative diseases. However, much less attention has been given to the death of glial cells. In this study, we examined p53-sensitive apoptosis of cells by using human glioblastoma A172 cells and p53-deficient mouse astrocytes. In human A172 cells, hydrogen peroxide (H2O2) caused cell death in a time- and concentration-dependent manner, accompanied by nucleosomal DNA fragmentation and chromatin condensation. After treatment with H2O2, p53 protein was highly expressed and protein levels of Bak, p21WAF1/CIP1 and GADD45 were also enhanced. However, the protein levels of Bcl-2 and Bax did not change. On the other hand, primary cultured astrocytes from p53-deficient mouse brain grew faster than wild-type and heterozygous astrocytes. In addition, p53-deficient astrocytes were more resistant to H2O2-induced apoptosis than wild-type and heterozygous astrocytes. These results suggest that glial proliferation and the repair of damaged DNA may be regulated by p53-induced p21WAF1/CIP1 and GADD45, and that glial apoptosis caused by oxidative stress may be mediated by p53-induced Bak.
现在人们普遍认为，氧化应激导致的大量神经元死亡是神经退行性疾病中大脑的一个常见特征。然而，神经胶质细胞的死亡却很少受到关注。在本研究中，我们使用人胶质母细胞瘤A172细胞和p53缺陷型小鼠星形胶质细胞来检测细胞的p53敏感性凋亡。在人A172细胞中，过氧化氢（H2O2）以时间和浓度依赖性方式导致细胞死亡，同时伴有核小体DNA片段化和染色质凝聚。用H2O2处理后，p53蛋白高度表达，Bak、p21WAF1/CIP1和GADD45的蛋白水平也升高。然而，Bcl-2和Bax的蛋白水平没有变化。另一方面，来自p53缺陷型小鼠脑的原代培养星形胶质细胞比野生型和杂合子星形胶质细胞生长得更快。此外，p53缺陷型星形胶质细胞比野生型和杂合子星形胶质细胞对H2O2诱导的凋亡更具抗性。这些结果表明，神经胶质细胞的增殖和受损DNA的修复可能受p53诱导的p21WAF1/CIP1和GADD45调控，并且氧化应激引起的神经胶质细胞凋亡可能由p53诱导的Bak介导。
