Pim-1 kinase activates Cdc25A phosphatase, the transcriptional target of c-Myc

皮姆-1癌基因编码丝氨酸/苏氨酸激酶（皮姆-1），参与细胞因子触发的有丝分裂信号的转导。Pim-1的独特之处在于它不仅在肿瘤发生过程中与c-Myc密切合作，而且在诱导细胞凋亡过程中也与c-Myc密切合作。然而，Pim-1功能的分子基础仍然知之甚少，主要是因为Pim-1激酶的下游效应分子尚未确定。在这里，我们提供了几条证据，证明Cdc25A细胞周期磷酸酶，c-Myc的直接转录靶点，是Pim-1激酶的底物，并作为Pim-1的效应物发挥作用。我们发现Pim-1在体内和体外都能与Cdc25A发生物理相互作用，并使Cdc25A磷酸化。我们还观察到pim -1介导的Cdc25A磷酸化增加了其磷酸酶活性。此外，野生型Pim-1，而不是激酶失活的Pim-1，增强了cdc25a介导的细胞转化和凋亡。我们的研究结果表明，Cdc25A可能是连接Pim-1和c-Myc的关键分子，也将Pim-1介导的有丝分裂信号与细胞周期机制联系起来。

The pim-1 oncogene encodes a serine/threonine kinase (Pim-1) involved in the transduction of cytokine-triggered mitogenic signals. Pim-1 is unique in that it closely cooperates with c-Myc not only in oncogenesis but also in apoptosis induction. However, the molecular basis of Pim-1 function remains poorly understood, largely because the downstream effector molecule (s) for Pim-1 kinase has not been identified. Here we provide several lines of evidence that Cdc25A cell cycle phosphatase, a direct transcriptional target for c-Myc, is a substrate for Pim-1 kinase and functions as an effector for Pim-1. We found that Pim-1 physically interacts with Cdc25A both in vitro and in vivo and phosphorylates Cdc25A.We also observed that Pim-1-mediated phosphorylation of Cdc25A increases its phosphatase activity. In addition, wild-type Pim-1, but not kinase-inactive Pim-1, enhanced Cdc25A-mediated cellular transformation and apoptosis. Our results indicate that Cdc25A might be a key molecule that links Pim-1 and c-Myc and also ties Pim-1-mediated mitogenic signals to cell cycle machinery.