Hayakawa Fumihiko, Privalsky Martin L
Section of Microbiology, Division of Biological Sciences, University of California at Davis, Davis, CA 95616, USA.
Cancer Cell. 2004 Apr;5(4):389-401. doi: 10.1016/s1535-6108(04)00082-0.
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).
早幼粒细胞白血病（PML）蛋白是一种强大的生长抑制因子和促凋亡因子，而PML与维甲酸受体（RAR）-α的异常融合是人类急性早幼粒细胞白血病的致病因素。三氧化二砷（As₂O₃）治疗通过一种尚未完全了解的机制诱导急性早幼粒细胞白血病细胞凋亡。我们在此报告，As₂O₃治疗通过丝裂原活化蛋白（MAP）激酶途径诱导PML蛋白磷酸化。PML磷酸化增加与PML的SUMO化增加以及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的磷酸化或SUMO化缺陷突变，会损害As₂O₃介导的PML细胞凋亡。我们得出结论，MAP激酶级联的磷酸化增强了PML的抗增殖功能，并有助于介导As₂O₃的促凋亡作用。
