Regulation of Wnt/beta-catenin pathway by cPLA2alpha and PPARdelta.
Regulation of Wnt/beta-catenin pathway by cPLA2alpha and PPARdelta.
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DOI：
10.1002/jcb.21852
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发表时间：
2008-10-01
影响因子：
4
通讯作者：
Wu, Tong
中科院分区：
文献类型：
--
作者：
Han, Chang;Lim, Kyu;Xu, Lihong;Li, Guiying;Wu, Tong
胞浆磷脂酶A2α(CPLA2α)是细胞膜磷脂释放花生四烯酸(AA)以产生前列腺素、白三烯和血小板活化因子等生物活性脂质介质的限速关键酶。CPLA2α在细胞内钙离子增加时被转移到核膜上，该酶也存在于细胞核内；然而，cPLA2α在细胞核中的生物学功能尚不清楚。在这里，我们展示了cPLA2α在激活细胞核中的过氧化物酶体增殖物激活受体δ(PPARδ)和β-连环蛋白中的新作用。CplA2α在人胆管癌细胞中的过表达可诱导PPARδ与β-连环蛋白的结合，并增加其与Tcf/Lef反应元件的关联性。这些作用可被cPLA2PPAR siRNA和抑制剂以及αδ的siRNA敲除所抑制。PPARδ的过表达或选择性PPARδ配体GW501516处理也增加了β-连环蛋白与Tcf/Lef反应元件的结合，并增加了其报告活性。在核提取液中加入AA和GW501516后，β-连环蛋白与Tcf/LEF反应元件的结合程度相当。此外，cPLA2α蛋白存在于δ和β-连环蛋白结合复合体中。因此，cPLA2α和PPARδ之间的紧密结合为它们在细胞核中的有效功能偶联提供了独特的优势，cPLA2α产生的AA立即可用于PPARδ结合和随后的β-连环蛋白激活。这些结果描绘了连接cplA2α、PPARδ和Wnt/β-catenin信号通路的一种新的相互作用，并为进一步了解这些关键分子在人类细胞和疾病中的作用提供了洞察力。
Cytosolic phospholipase A2α (cPLA2α) is a rate-limiting key enzyme that releases arachidonic acid (AA) from membrane phospholipid for the production of biologically active lipid mediators including prostaglandins, leukotrienes and platelet-activating factor. cPLA2α is translocated to nuclear envelope in response to intracellular calcium increase and the enzyme is also present inside the cell nucleus; however, the biological function of cPLA2α in the nucleus remains unknown. Here we show a novel role of cPLA2α for activation of peroxisome proliferator-activated receptor-δ (PPARδ) and β-catenin in the nuclei. Overexpression of cPLA2α in human cholangiocarcinoma cells induced the binding of PPARδ to β-catenin and increased their association with the TCF/LEF response element. These effects are inhibited by the cPLA2α siRNA and inhibitors as well as by siRNA knockdown of PPARδ. Overexpression of PPARδ or treatment with the selective PPARδ ligand, GW501516, also increased β-catenin binding to TCF/LEF response element and increased its reporter activity. Addition of AA and GW501516 to nuclear extracts induced a comparable degree of β-catenin binding to TCF/LEF response element. Furthermore, cPLA2α protein is present in the PPARδ and β-catenin binding complex. Thus the close proximity between cPLA2α and PPARδ provides a unique advantage for their efficient functional coupling in the nucleus, where AA produced by cPLA2α comes immediately available for PPARδ binding and subsequent β-catenin activation. These results depict a novel interaction linking cPLA2α, PPARδ and Wnt/β-catenin signaling pathways and provide insight for further understanding the roles of these key molecules in human cells and diseases.
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