Pim Kinases Promote Cell Cycle Progression by Phosphorylating and Down-regulating p27Kip1 at the Transcriptional and Posttranscriptional Levels

摘要: The serine/threonine kinase Pim is known to promote cell cycle progression and inhibit apoptosis leading tumorigenesis. However, the precise mechanisms remain unclear. We show, herein, that all family members (Pim1, Pim2, Pim3) bind directly phosphorylate cyclin-dependent inhibitor p27 Kip1 at threonine-157 threonine-198 residues in cells vitro . Pim-mediated phosphorylation induced binding 14-3-3 protein, resulting its nuclear export proteasome-dependent degradation. Ectopic expression of kinases overcome G 1 arrest mediated by wild-type but not phosphorylation-resistant T157A-p27 or T198A-p27 In addition posttranslational regulations, promoter assay revealed also had ability suppress transcription. inactivation forkhead transcription factors, FoxO1a FoxO3a, was involved transcriptional repression gene. contrast, inhibition signaling expressing dominant-negative form Pim1 increased level attenuated proliferation. Because CDK plays a crucial role tumor suppression inhibiting abnormal progression, tumorigenesis down-regulating both levels. [Cancer Res 2008;68(13):5076–85]