title: Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity.
abstract: Group IVA phospholipase A2 [cytosolic phospholipase A2α (cPLA2α)] is a key mediator of inflammation and tumorigenesis. In this study, by using a combination of chemical inhibition and genetic approaches in zebrafish and murine cells, we identify a mechanism by which cPLA2α promotes cell proliferation. We identified 2 cpla2α genes in zebrafish, cpla2αa and cpla2αb, with conserved phospholipase activity. In zebrafish, loss of cpla2α expression or inhibition of cpla2α activity diminished G1 progression through the cell cycle. This phenotype was also seen in both mouse embryonic fibroblasts and mesangial cells. G1 progression was rescued by the addition of arachidonic acid or prostaglandin E2 (PGE2), indicating a phospholipase-dependent mechanism. We further show that PGE2, through PI3K/AKT activation, promoted Forkhead box protein O1 (FOXO1) phosphorylation and FOXO1 nuclear export. This led to up-regulation of cyclin D1 and down-regulation of p27(Kip1), thus promoting G1 progression. Finally, using pharmacologic inhibitors, we show that cPLA2α, rapidly accelerated fibrosarcoma (RAF)/MEK/ERK, and PI3K/AKT signaling pathways cooperatively regulate G1 progression in response to platelet-derived growth factor stimulation. In summary, these data indicate that cPLA2α, through its phospholipase activity, is a critical effector of G1 phase progression through the cell cycle and suggest that pharmacological targeting of this enzyme may have important therapeutic benefits in disease mechanisms that involve excessive cell proliferation, in particular, cancer and proliferative glomerulopathies.
authors.affiliation: *Renal Division, Brigham and Women's Hospital, Department of Medicine, and Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Amiens Southern Hospital, Amiens, France; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; and Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Said Movahedi
authors.initials: SM
authors.lastname: Naini
authors.affiliation: *Renal Division, Brigham and Women's Hospital, Department of Medicine, and Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Amiens Southern Hospital, Amiens, France; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; and Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Choukroun
authors.affiliation: *Renal Division, Brigham and Women's Hospital, Department of Medicine, and Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Amiens Southern Hospital, Amiens, France; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; and Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Ryan
authors.affiliation: *Renal Division, Brigham and Women's Hospital, Department of Medicine, and Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Amiens Southern Hospital, Amiens, France; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; and Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hentschel
authors.affiliation: *Renal Division, Brigham and Women's Hospital, Department of Medicine, and Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Amiens Southern Hospital, Amiens, France; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; and Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jagesh V
authors.initials: JV
authors.lastname: Shah
authors.affiliation: *Renal Division, Brigham and Women's Hospital, Department of Medicine, and Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Amiens Southern Hospital, Amiens, France; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA; and Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA joseph_bonventre@hms.harvard.edu.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D015027:Zebrafish
chemical_list: D051858:Forkhead Transcription Factors; D010982:Platelet-Derived Growth Factor; D016718:Arachidonic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D054513:Group IV Phospholipases A2; D015232:Dinoprostone
keywords: PGE2; cell cycle; cyclin D1; p27Kip1; zebrafish