Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity-猫眼课题宝

DOI：

10.1096/fj.15-278416

发表时间：

2016-03

期刊：

The FASEB Journal

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

S. Naini;G. Choukroun;James R. Ryan;Dirk M. Hentschel;J. Shah;J. Bonventre

IVA 族磷脂酶 A2 [胞质磷脂酶 A2α (cPLA2α)] 是炎症和肿瘤发生的关键介质。在这项研究中，通过在斑马鱼和小鼠细胞中结合使用化学抑制和遗传方法，我们确定了 cPLA2α 促进细胞增殖的机制。我们在斑马鱼中鉴定出 2 个 cpla2α 基因，即 cpla2αa 和 cpla2αb，具有保守的磷脂酶活性。在斑马鱼中，cpla2α 表达的丧失或 cpla2α 活性的抑制会减少细胞周期中 G1 期的进展。这种表型也在小鼠胚胎成纤维细胞和系膜细胞中观察到。添加花生四烯酸或前列腺素 E2 (PGE2) 可挽救 G1 进展，表明磷脂酶依赖性机制。我们进一步表明，PGE2 通过 PI3K/AKT 激活，促进 Forkhead box 蛋白 O1 (FOXO1) 磷酸化和 FOXO1 核输出。这导致细胞周期蛋白 D1 上调和 p27Kip1 下调，从而促进 G1 进展。最后，使用药物抑制剂，我们发现 cPLA2α、快速加速纤维肉瘤 (RAF)/MEK/ERK 和 PI3K/AKT 信号通路协同调节 G1 进展，以响应血小板源性生长因子的刺激。总之，这些数据表明，cPLA2α 通过其磷脂酶活性，是细胞周期 G1 期进展的关键效应子，并表明该酶的药理学靶向可能对涉及细胞过度增殖的疾病机制（特别是癌症和增殖性肾小球病）具有重要的治疗益处。-Naini, S. M., Choukroun, G. J., Ryan, J. R., Hentschel, D. M., Shah, J. V., Bonventre, J. V.，胞浆磷脂酶 A2α 通过调节 FOXO1 活性来调节 G1 进程。 FASEB J. 30, 1155–1170 (2016)。 www.fasebj.org

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.—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. FASEB J. 30, 1155–1170 (2016). www.fasebj.org

Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity

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