Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase - Implications for the Pim-1-mediated activation of the c-Myc signaling pathway

The pim-1 oncogene encodes a serine/threonine kinase (Pim-1) involved in th e 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 evi dence that Cdc25A cell cycle phosphatase, a direct transcriptional target f or 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 a nd 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 ce llular transformation and apoptosis, Our results indicate that Cdc25A might be a key molecule that links Pim-1 and c-Myc and that also ties Pim-1-medi ated mitogenic signals to cell cycle machinery.