title: The Plant Hormone Abscisic Acid Is a Prosurvival Factor in Human and Murine Megakaryocytes.
abstract: Abscisic acid (ABA) is a phytohormone involved in pivotal physiological functions in higher plants. Recently, ABA has been proven to be also secreted and active in mammals, where it stimulates the activity of innate immune cells, mesenchymal and hematopoietic stem cells, and insulin-releasing pancreatic β cells through a signaling pathway involving the second messenger cyclic ADP-ribose (cADPR). In addition to behaving like an animal hormone, ABA also holds promise as a nutraceutical plant-derived compound in humans. Many biological functions of ABA in mammals are mediated by its binding to the LANCL-2 receptor protein. A putative binding of ABA to GRP78, a key regulator of endoplasmic reticulum stress, has also been proposed. Here we investigated the role of exogenous ABA in modulating thrombopoiesis, the process of platelet generation. Our results demonstrate that expression of both LANCL-2 and GRP78 is up-regulated during hematopoietic stem cell differentiation into mature megakaryocytes (Mks). Functional ABA receptors exist in mature Mks because ABA induces an intracellular Ca2+increase ([Ca2+]i) through PKA activation and subsequent cADPR generation.In vitroexposure of human or murine hematopoietic progenitor cells to 10 μm ABA does not increase recombinant thrombopoietin (rTpo)-dependent Mk differentiation or platelet release. However, under conditions of cell stress induced by rTpo and serum deprivation, ABA stimulates, in a PKA- and cADPR-dependent fashion, the mitogen-activated kinase ERK 1/2, resulting in the modulation of lymphoma 2 (Bcl-2) family members, increased Mk survival, and higher rates of platelet production. In conclusion, we demonstrate that ABA is a prosurvival factor for Mks in a Tpo-independent manner.
authors.affiliation: Departments of Molecular Medicine, Laboratories of Biotechnology, IRCCS San Matteo Foundation.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Malara
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genova, Genova 16132, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fresia
authors.affiliation: Departments of Molecular Medicine, Laboratories of Biotechnology, IRCCS San Matteo Foundation.
authors.forename: Christian Andrea
authors.initials: CA
authors.lastname: Di Buduo
authors.affiliation: Departments of Molecular Medicine, Laboratories of Biotechnology, IRCCS San Matteo Foundation.
authors.forename: Paolo Maria
authors.initials: PM
authors.lastname: Soprano
authors.affiliation: Biology and Biotechnology, University of Pavia, Pavia 27100, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Moccia
authors.affiliation: Biology and Biotechnology, University of Pavia, Pavia 27100, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Balduini
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genova, Genova 16132, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Zocchi
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genova, Genova 16132, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: De Flora
authors.affiliation: Departments of Molecular Medicine, Laboratories of Biotechnology, IRCCS San Matteo Foundation; Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155. Electronic address: alessandra.balduini@unipv.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Balduini
mesh_terms: D000040:Abscisic Acid / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D010937:Plant Growth Regulators / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D034061:Thrombopoiesis / Q000187:drug effects*; D013926:Thrombopoietin / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C471704:LANCL2 protein, human; C572254:LANCL2 protein, mouse; D008565:Membrane Proteins; D009687:Nuclear Proteins; D028044:Phosphate-Binding Proteins; D010937:Plant Growth Regulators; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D000040:Abscisic Acid; D013926:Thrombopoietin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium
keywords: B cell lymphoma 2 (Bcl-2) family; ERK; PKA; abscisic acid (ABA); calcium; cyclic ADP Ribose (cADPR); megakaryocyte; thrombopoiesis