PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression.
PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors and hormones. It has been implicated in the control of cell cycle progression and apoptosis and its overexpression has been associated with various kinds of lymphoid and hematopoietic malignancies. The activity of PIM1 is dependent on the phosphorylation of several targets involved in transcription, cell cycle and apoptosis. We have recently observed that PIM1 interacts with ribosomal protein (RP)S19 and cosediments with ribosomes. Defects in ribosome synthesis (ribosomal stress) have been shown to activate a p53-dependent growth arrest response. To investigate if PIM1 could have a role in the response to ribosomal stress, we induced ribosome synthesis alterations in TF-1 and K562 erythroid cell lines. We found that RP deficiency, induced by RNA interference or treatment with inhibitor of nucleolar functions, causes a drastic destabilization of PIM1. The lower level of PIM1 induces an increase in the cell cycle inhibitor p27(Kip1) and blocks cell proliferation even in the absence of p53. Notably, restoring PIM1 level by transfection causes a recovery of cell growth. Our data indicate that PIM1 may act as a sensor for ribosomal stress independently of or in concert with the known p53-dependent mechanisms.
Iadevaia
V
V
Department of Biology, University Tor Vergata, Roma, Italy.
Caldarola
S
S
Biondini
L
L
Gismondi
A
A
Karlsson
S
S
Dianzani
I
I
Loreni
F
F
D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C040343:ribosomal protein S19; D050760:Cyclin-Dependent Kinase Inhibitor p27; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1