title: PIM1 destabilization activates a p53-dependent response to ribosomal stress in cancer cells.
abstract: Defects in ribosome biogenesis triggers a stress response (ribosomal stress) that can lead to growth arrest and apoptosis. Signaling pathways activated by ribosomal stress are specifically involved in the pathological mechanism of a group of disorders defined as ribosomopathies. However, more generally, the quality control of ribosome synthesis is part of the regulatory circuits that control cell metabolism. A number of studies identified tumor suppressor p53 as a central player in ribosomal stress. We have previously reported that the kinase PIM1 plays a role as a sensor for ribosome deficiency. In this report we address the relationship between PIM1 and p53 in cancer cell lines after depletion of a ribosomal protein. We identified a novel signaling pathway that includes the kinase AKT and the ubiquitin ligase MDM2. In fact, our results indicate that the lower level of PIM1, induced by ribosomal stress, causes inactivation of AKT, inhibition of MDM2 and a consequent p53 stabilization. Therefore, we propose that activation of p53 in response to ribosomal stress, is dependent on the pathway PIM1-AKT-MDM2. In addition, we report evidence that PIM1 level may be relevant to assess the sensitivity of cancer cells to chemotherapeutic drugs that induce ribosomal stress.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Roma, Italy.
authors.forename: Vinay
authors.initials: V
authors.lastname: Sagar
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Roma, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Caldarola
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Roma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Aria
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Roma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Monteleone
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Roma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fuoco
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Roma, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Gargioli
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Roma, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cannata
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Roma, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loreni
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000737:chemistry* / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051058:Oncogene Protein v-akt; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: AKT; MDM2; PIM1; p53; ribosomal stress