Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53
Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53
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DOI：
10.1038/sj.cdd.4401768
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发表时间：
2006-03-01
影响因子：
12.4
通讯作者：
Hosoi, Y
中科院分区：
文献类型：
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作者：
Morita, A;Zhu, J;Hosoi, Y
我们以前报道过，p42/SET β是照射MOLT-4细胞中caspase-7的底物，用原钒酸钠（钒酸盐）处理细胞抑制p42/SET β的caspase介导的裂解。在这里，我们最初发现，钒酸盐的抑制作用是由于抑制半胱天冬酶的激活，但不是半胱天冬酶的活性。进一步的研究表明，钒酸盐抑制上游的凋亡事件，如线粒体膜电位的损失，Bax的构象变化，和p53的反式激活，虽然积累，总磷酸化，和磷酸化的6个单独的网站p53不受影响。重要的是，钒酸盐抑制p53依赖性细胞凋亡，但不抑制p53非依赖性细胞凋亡。最后，凝胶位移和染色质免疫沉淀试验最终证明，钒酸盐抑制DNA结合活性的p53。钒酸盐通常被用作蛋白酪氨酸磷酸酶（PTPs）的抑制剂;然而，我们建议在使用它之前，不仅要考虑钒酸盐对PTPs的影响，还要考虑它对p53的影响。
We previously reported that p42/SET beta is a substrate for caspase-7 in irradiated MOLT-4 cells, and that treating the cells with sodium orthovanadate (vanadate) inhibits p42/SET beta's caspase-mediated cleavage. Here, we initially found that the inhibitory effect of vanadate was due to the suppression of caspase activation but not of caspase activity. Further investigations revealed that vanadate suppressed upstream of apoptotic events, such as the loss of mitochondrial membrane potential, the conformational change of Bax, and p53 transactivation, although the accumulation, total phosphorylation, and phosphorylation of six individual sites of p53 were not affected. Importantly, vanadate suppressed p53-dependent apoptosis, but not p53-independent apoptosis. Finally, gel-shift and chromatin immunoprecipitation assays conclusively demonstrated that vanadate inhibits the DNA-binding activity of p53. Vanadate is conventionally used as an inhibitor of protein tyrosine phosphatases (PTPs); however, we recommend that the influence of vanadate not only on PTPs but also on p53 be considered before using it.