Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis
Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis
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DOI：
10.1016/s1535-6108(04)00082-0
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发表时间：
2004-04-01
期刊：
影响因子：
50.3
通讯作者：
Privalsky, ML
中科院分区：
文献类型：
--
作者：
Hayakawa, F;Privalsky, ML
早幼粒细胞白血病 (PML) 蛋白是一种有效的生长抑制因子和促凋亡因子，而 PML 和视黄酸受体 (RAR)-α 的异常融合是人类急性早幼粒细胞白血病的致病因子。三氧化二砷 (AS(2)O(3)) 治疗通过一种不完全了解的机制诱导急性早幼粒细胞白血病细胞凋亡。我们在此报道 AS(2)O(3) 治疗通过丝裂原激活蛋白 (MAP) 激酶途径诱导 PML 蛋白磷酸化。 PML 磷酸化增加与 PML 苏酰化增加和 PML 介导的细胞凋亡增加相关。相反，MAP激酶级联抑制剂或引入PML磷酸化或SUMO化缺陷突变，会损害AS(2)O(3)介导的PML细胞凋亡。我们得出的结论是，MAP 激酶级联磷酸化可增强 PML 的抗增殖功能，并有助于介导 AS(2)O(3) 的促凋亡作用。
The promyelocytic leukemia (PML) protein is a potent growth suppressor and proapototic factor, whereas aberrant fusions of PML and retinoic acid receptor (RAR)-alpha are causal agents in human acute promyelocytic leukemia. Arsenic trioxide (AS(2)O(3)) treatment induces apoptosis in acute promyelocytic leukemia cells through an incompletely understood mechanism. We report here that AS(2)O(3) treatment induces phosphorylation of the PML protein through a mitogen-activated protein (MAP) kinase pathway. Increased PML phosphorylation is associated with increased sumoylation of PML and increased PML-mediated apoptosis. Conversely, MAP kinase cascade inhibitors, or the introduction of phosphorylation or sumoylation-defective mutations of PML, impair AS(2)O(3)-mediated apoptosis by PML. We conclude that phosphorylation by MAP kinase cascades potentiates the antiproliferative functions of PML and helps mediate the proapoptotic effects of AS(2)O(3).