title: Lysophosphatidic acid induces Ca2+ mobilization and c-Myc expression in mouse embryonic stem cells via the phospholipase C pathway.
abstract: Embryonic stem cells (ESC) are pluripotent and could be maintained in vitro in a self-renewing state indefinitely, at the same time preserving their potential to differentiate towards more specific lineages. Despite the progress in the field, the complex network of signalling cascades involved in the maintenance of the self-renewing and pluripotent state remains not fully understood. In the present study, we have investigated the role of lysophosphatidic acid (LPA), a potent mitogen present in serum, in Ca(2+) signalling and early gene activation in mouse ESC (mESC). In these cells, we detected the expression of the G-protein coupled LPA receptor subtypes LPA(1), LPA(2) and LPA(3). Using fluorescence Ca(2+) imaging techniques, we showed that LPA induced an increase in intracellular Ca(2+) concentration. This increase was also observed in the absence of extracellular Ca(2+), suggesting the involvement of internal stores. Pre-treatment with BAPTA-AM, thapsigargin or U-73122 efficiently blocked this Ca(2+) release, indicating that LPA was evoking Ca(2+) mobilization from the endoplasmic reticulum via the phospholipase C (PLC) pathway. Interestingly, this signalling cascade initiated by LPA was involved in inducing the expression of the Ca(2+)-dependent early response gene c-myc, a key gene implicated in ESC self-renewal and pluripotency. Additionally, LPA increased the proliferation rate of mESC. Our findings therefore outline the physiological role of LPA in mESC.
authors.affiliation: Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, 03202 Elche, Alicante, Spain.
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Todorova
authors.forename: Esther
authors.initials: E
authors.lastname: Fuentes
authors.forename: Bernat
authors.initials: B
authors.lastname: Soria
authors.forename: Angel
authors.initials: A
authors.lastname: Nadal
authors.forename: Ivan
authors.initials: I
authors.lastname: Quesada
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D002451:Cell Compartmentation; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects*; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D004963:Estrenes; D008246:Lysophospholipids; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011760:Pyrrolidinones; D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D019284:Thapsigargin; D010738:Type C Phospholipases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C032881:lysophosphatidic acid