PUBLICATION
Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity
- Authors
- Naini, S.M., Choukroun, G.J., Ryan, J.R., Hentschel, D.M., Shah, J.V., Bonventre, J.V.
- ID
- ZDB-PUB-151209-2
- Date
- 2016
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30(3): 1155-70 (Journal)
- Registered Authors
- Keywords
- PGE2, cell cycle, cyclin D1, p27Kip1, zebrafish
- MeSH Terms
-
- Animals
- Arachidonic Acid/pharmacology
- Cell Division/drug effects
- Cell Line
- Cell Proliferation/drug effects
- Dinoprostone/pharmacology
- Down-Regulation/drug effects
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Forkhead Transcription Factors/metabolism*
- G1 Phase/drug effects
- G1 Phase/physiology*
- Group IV Phospholipases A2/genetics
- Group IV Phospholipases A2/metabolism*
- HEK293 Cells
- Humans
- Mice
- Phosphatidylinositol 3-Kinases/genetics
- Phosphatidylinositol 3-Kinases/metabolism
- Phosphorylation/drug effects
- Platelet-Derived Growth Factor/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Signal Transduction/drug effects
- Up-Regulation/drug effects
- Zebrafish
- PubMed
- 26644349 Full text @ FASEB J.
Citation
Naini, S.M., Choukroun, G.J., Ryan, J.R., Hentschel, D.M., Shah, J.V., Bonventre, J.V. (2016) Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 30(3):1155-70.
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.-Naini, S. M., Choukroun, G. J., Ryan, J. R., Hentschel, D. M., Shah, J. V., Bonventre, J. V. Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping