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- Title
Cytosolic phospholipase A<sub>2</sub>α regulates G<sub>1</sub> progression through modulating FOXO1 activity.
- Authors
Naini, Said Movahedi; Choukroun, Gabriel J.; Ryan, James R.; Hentsche, Dirk M.; Shah, Jagesh V.; Bonventre, Joseph V.
- 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 p27Kip1, 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.
- Subjects
CYTOSOL; PHOSPHOLIPASE A2; GENE expression; ENZYME activation; CHEMICAL inhibitors; NEOPLASTIC cell transformation
- Publication
FASEB Journal, 2016, Vol 30, Issue 3, p1155
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.15-278416