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Title: Altered regulation of the Spry2/Dyrk1A/PP2A triad by homocysteine impairs neural progenitor cell proliferation.
Authors: Rabaneda, Luis G
Geribaldi-Doldán, Noelia
Murillo-Carretero, Maribel
Carrasco, Manuel
Martínez-Salas, José M
Verástegui, Cristina
Castro, Carmen
Keywords: Dyrk1A;PP2A;Spry2;homocysteine;neural progenitor cells;neurogenesis
metadata.dc.subject.mesh: Animals
Cell Proliferation
Cyclin E
DNA Methylation
Gene Expression Regulation, Developmental
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Neural Stem Cells
Promoter Regions, Genetic
Protein Phosphatase 2
Protein Serine-Threonine Kinases
Protein Stability
Protein-Tyrosine Kinases
RNA, Messenger
Receptors, Fibroblast Growth Factor
Signal Transduction
Spheroids, Cellular
Issue Date: 26-Sep-2016
Abstract: Hyperhomocysteinemia reduces neurogenesis in the adult mouse brain. Homocysteine (Hcy) inhibits postnatal neural progenitor cell (NPC) proliferation by specifically impairing the fibroblast growth factor receptor (FGFR)-Erk1/2-cyclin E signaling pathway. We demonstrate herein that the inhibition of FGFR-dependent NPC proliferation induced by Hcy is mediated by its capacity to alter the cellular methylation potential. Our results show that this alteration modified the expression pattern and activity of Sprouty2 (Spry2), a negative regulator of the above mentioned pathway. Both elevated concentrations of Hcy and methyltransferase activity inhibition induced Spry2 promoter demethylation in NPC cultures leading to a sustained upregulation of the expression of Spry2 mRNA and protein. In addition, protein levels of two kinases responsible for Spry2 activation/deactivation were altered by Hcy: Spry2 kinase Dyrk1A levels diminished while Spry2 phosphatase PP2A increased, leading to changes in the phosphorylation pattern, activity and stability of Spry2. In conclusion, Hcy inhibits NPC proliferation by indirect mechanisms involving alterations in DNA methylation, gene expression, and Spry2 function, causing FGFR signaling impairment.
metadata.dc.identifier.doi: 10.1016/j.bbamcr.2016.09.018
ISSN: 0006-3002
Appears in Collections:Producción 2020

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