Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels.
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 p27(Kip1) at threonine-157 and threonine-198 residues in cells and in vitro. The Pim-mediated phosphorylation induced p27(Kip1) binding to 14-3-3 protein, resulting in its nuclear export and proteasome-dependent degradation. Ectopic expression of Pim kinases overcome the G(1) arrest mediated by wild-type p27(Kip1) but not by phosphorylation-resistant T157A-p27(Kip1) or T198A-p27(Kip1). In addition to the posttranslational regulations, p27(Kip1) promoter assay revealed that Pim kinases also had the ability to suppress p27(Kip1) transcription. Pim-mediated phosphorylation and inactivation of forkhead transcription factors, FoxO1a and FoxO3a, was involved in the transcriptional repression of the p27(Kip1) gene. In contrast, inhibition of Pim signaling by expressing the dominant-negative form of Pim1 increased nuclear p27(Kip1) level and attenuated cell proliferation. Because the CDK inhibitor p27(Kip1) plays a crucial role in tumor suppression by inhibiting abnormal cell cycle progression, Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels.
Morishita
Daisuke
D
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, The University of Tokyo, Tokyo, Japan.
Katayama
Ryohei
R
Sekimizu
Kazuhisa
K
Tsuruo
Takashi
T
Fujita
Naoya
N
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016384:Consensus Sequence; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013912:Threonine; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim