Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis

The promyelocytic leukemia (PML) protein is a potent growth suppressor and proapototic factor, whereas aberrant fusions of PML and retinoic acid receptor (RAR)-α are causal agents in human acute promyelocytic leukemia. Arsenic trioxide (As₂O₃) treatment induces apoptosis in acute promyelocytic leukemia cells through an incompletely understood mechanism. We report here that As₂O₃ 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 As₂O₃-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 ₂O₃.