PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression

Abstract

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.

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

“…In human cancer cell lines, p53-independent mechanisms linking ribosome biogenesis defects to cell cycle arrest have been reported. 44,45 Interestingly, binding of RPL11 to MDM2 was shown to inhibit its E2F1-stabilizing activity, thereby hindering cell cycle progression. 44 Increased binding of RPL11 to MDM2 consecutive to ribosome biogenesis dysfunction could therefore potentially interfere with other p53-independent functions of MDM2 such as inhibition of apoptosis.…”

Translation factors and ribosomal proteins control tumor onset and progression: how?

“…141,[157][158][159][160][161][162][163] However, in addition to the p53-dependent mechanisms, other possible signaling molecules are thought to mediate growth inhibitory effects of ribosomal stress independently of p53. 156,164,165 The best evidence of p53 involvement in the response to ribosomal stress is that p53 suppression by genetical or biochemical means in experimental model systems can rescue at least part of the defects caused by ribosome alteration. 141,157,162,166 To explain the relationship Figure 4.…”

“…Similar effects could be mediated by the kinase PIM1, recently shown to be involved in the response to ribosomal stress. 156 Although considerably speculative, this hypothesis could apply to all the ribosomopathies, including those involving ribosome biogenesis factors such as Schwachman-Diamond syndrome, cartilage hair hypoplasia, Treacher Collins syndrome.…”

Nanodiamonds coupled with 5,7-dimethoxycoumarin, a plant bioactive metabolite, interfere with the mitotic process in B16F10 cells altering the actin organization

“…Then, cDNA was synthesized, PCR amplifications were performed, and the amount of mRNA for each gene was determined, as reported by Iadevaia et al 24 In particular, the primer pairs used in the present work are extensively described in Figure S1.…”