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Eukaryotic translation initiation factor 6 is a novel regulator of reactive oxygen species-dependent megakaryocyte maturation.
Ricciardi, S; Miluzio, A; Brina, D; Clarke, K; Bonomo, M; Aiolfi, R; Guidotti, L G; Falciani, F; Biffo, S.
Afiliación
  • Ricciardi S; Molecular Histology and Cell Growth Unit, National Institute of Molecular Genetics - INGM, 'Romeo ed Enrica Invernizzi', Milan, Italy.
  • Miluzio A; Molecular Histology and Cell Growth Unit, National Institute of Molecular Genetics - INGM, 'Romeo ed Enrica Invernizzi', Milan, Italy.
  • Brina D; Molecular Histology and Cell Growth Unit, National Institute of Molecular Genetics - INGM, 'Romeo ed Enrica Invernizzi', Milan, Italy.
  • Clarke K; Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
  • Bonomo M; Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
  • Aiolfi R; Immunopathology Unit, San Raffaele Scientific Institute, Milan, Italy.
  • Guidotti LG; Immunopathology Unit, San Raffaele Scientific Institute, Milan, Italy.
  • Falciani F; Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
  • Biffo S; Molecular Histology and Cell Growth Unit, National Institute of Molecular Genetics - INGM, 'Romeo ed Enrica Invernizzi', Milan, Italy.
J Thromb Haemost ; 13(11): 2108-18, 2015 Nov.
Article en En | MEDLINE | ID: mdl-26391622
BACKGROUND: Ribosomopathies constitute a class of inherited disorders characterized by defects in ribosome biogenesis and function. Classically, bone marrow (BM) failure is a clinical symptom shared between these syndromes, including Shwachman-Bodian-Diamond syndrome (SBDS). Eukaryotic translation initiation factor 6 (eIF6) is a critical translation factor that rescues the quasilethal effect of the loss of the SBDS protein. OBJECTIVES: To determine whether eIF6 activity is necessary for BM development. METHODS: We used eIF6(+/-) mice and primary BM megakaryocytes to investigate the involvement of eIF6 in the regulation of hematopoiesis. RESULTS: We provide evidence that reduced eIF6 expression negatively impacts on megakaryopoiesis. We show that inhibition of eIF6 leads to a reduction in cell size and mean ploidy level of megakaryocytes and a delay in megakaryocyte maturation by blocking the G1 /S transition. Consistent with this phenotype, only few megakaryocyte-forming proplatelets were found in eIF6(+/-) cells. We also discovered that, in eIF6(+/-) cells, the steady-state abundance of mitochondrial respiratory chain complex I-encoding mRNAs is decreased, resulting in decreased reactive oxygen species (ROS) production. Intriguingly, connectivity map analysis showed that eIF6-mediated changes overlap with specific translational inhibitors. eIF6 is a translation factor acting downstream of insulin/phorbol 12-myristate 13-acetate (PMA) stimulation. PMA treatment significantly restored eIF6(+/-) megakaryocyte maturation, indicating that activation of eIF6 is essential for the rescue of the phenotype. CONCLUSIONS: Taken together, our results show a role for eIF6-driven translation in megakaryocyte development, and unveil the novel connection between translational control and ROS production in this cell subset.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Iniciación de Péptidos / Especies Reactivas de Oxígeno / Trombopoyesis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2015 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Iniciación de Péptidos / Especies Reactivas de Oxígeno / Trombopoyesis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2015 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido