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Molecular Biology, Pathobiology, and Genetics |
1 Cancer Chemotherapy Center, Japanese Foundation for Cancer Research and 2 Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
Requests for reprints: Naoya Fujita, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan. Phone: 81-33570-0468; Fax: 81-3-3570-0484; E-mail: naoya.fujita{at}jfcr.or.jp.
Key Words: Pim kinase p27Kip1 FoxO transcription factor cell cycle cancer chemotherapy
The serine/threonine kinase Pim is known to promote cell cycle progression and to inhibit apoptosis leading to tumorigenesis. However, the precise mechanisms remain unclear. We show, herein, that all the Pim family members (Pim1, Pim2, and Pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27Kip1 at threonine-157 and threonine-198 residues in cells and in vitro. The Pim-mediated phosphorylation induced p27Kip1 binding to 14-3-3 protein, resulting in its nuclear export and proteasome-dependent degradation. Ectopic expression of Pim kinases overcome the G1 arrest mediated by wild-type p27Kip1 but not by phosphorylation-resistant T157A-p27Kip1 or T198A-p27Kip1. In addition to the posttranslational regulations, p27Kip1 promoter assay revealed that Pim kinases also had the ability to suppress p27Kip1 transcription. Pim-mediated phosphorylation and inactivation of forkhead transcription factors, FoxO1a and FoxO3a, was involved in the transcriptional repression of the p27Kip1 gene. In contrast, inhibition of Pim signaling by expressing the dominant-negative form of Pim1 increased nuclear p27Kip1 level and attenuated cell proliferation. Because the CDK inhibitor p27Kip1 plays a crucial role in tumor suppression by inhibiting abnormal cell cycle progression, Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27Kip1 expression at both transcriptional and posttranslational levels. [Cancer Res 2008;68(13):5076–85]
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