Timing and Expression Level of Protein Kinase Cε Regulate the Megakaryocytic Differentiation of Human CD34 Cells

Authors

  • Giuliana Gobbi,

    1. Department of Anatomy, Pharmacology & Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, via Gramsci, Parma, Italy
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  • Prisco Mirandola,

    1. Department of Anatomy, Pharmacology & Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, via Gramsci, Parma, Italy
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  • Ivonne Sponzilli,

    1. Department of Anatomy, Pharmacology & Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, via Gramsci, Parma, Italy
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  • Cristina Micheloni,

    1. Department of Anatomy, Pharmacology & Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, via Gramsci, Parma, Italy
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  • Chiara Malinverno,

    1. Department of Anatomy, Pharmacology & Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, via Gramsci, Parma, Italy
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  • Lucio Cocco,

    1. Cellular Signalling Laboratory, Department of Anatomical Sciences, University of Bologna, Bologna, Italy
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  • Marco Vitale M.D.

    Corresponding author
    1. Department of Anatomy, Pharmacology & Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, via Gramsci, Parma, Italy
    2. Istituto di Genetica Molecolare-Consiglio Nazionale delle Ricerche, Unit of Bologna, c/o Istituti Ortopedici Rizzoli, Bologna, Italy
    • Department of Anatomy, Pharmacology & Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, Via Gramsci, 14, I-43100 Parma, Italy. Telephone: +39.0521.033032; Fax: +39.0521.033033
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Abstract

Protein kinase C (PKC)-mediated intracellular signaling participates in several key steps of hematopoietic cell differentiation. The ε isoform of PKC has been associated with erythroid differentiation as well as with the early phases of megakaryocytic (MK) lineage commitment. Here, we worked on the hypothesis that PKCε expression levels might be modulated during MK differentiation, with a specific role in the early as well as in the late phases of thrombopoiesis. We demonstrate that—at variance with the erythroid lineage development—PKCε is completely downmodulated in TPO-induced CD34 cells from day 6 onward. The forced expression of PKCε in the late phases of MK differentiation delays the phenotypic differentiation of progenitors likely via Bcl-xL upregulation. Moreover, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), known as a negative regulator of early erythroid expansion, is not apoptogenic for thrombopoietin-induced CD34 cells, but rather accelerates their maturation. However, PKCε levels negatively interfere also with the effects of TRAIL in MK differentiation. PKCε can therefore be considered a signaling intermediate whose expression levels are finely tuned, with a virtually opposite kinetic, in erythroid versus megakaryocytic lineages, to adequately respond to the signaling requirements of the specific hematopoietic lineage.

Disclosure of potential conflicts of interest is found at the end of this article.

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