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doi: 10.1242/10.1242/jcs.00146

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Nuclear localisation of cytosolic phospholipase A₂- in the EA.hy.926 human endothelial cell line is proliferation dependent and modulated by phosphorylation

¹ School of Biochemistry and Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
² Cancer Research UK Clinical Centre, St. James' Hospital, University of Leeds, Leeds, LS9 7TF, UK

^* Author for correspondence (e-mail: j.h.walker{at}leeds.ac.uk)

Accepted 4 September 2002

Cytosolic phospholipase A₂- (cPLA₂-) is a calcium-sensitive enzyme involved in receptor-mediated eicosanoid production. In resting cells, cPLA₂- is present in the cytosol and nucleus and translocates to membranes via its calcium-dependent lipid-binding (CaLB) domain following stimulation. cPLA₂- is also regulated by phosphorylation on several residues, which results in enhanced arachidonic acid release. Little is known about the factors controlling the nuclear localisation of cPLA₂-. Here the nuclear localisation of cPLA₂- in the EA.hy.926 human endothelial cell line was investigated. Nuclear localisation was dependent on proliferation, with subconfluent cells containing higher levels of nuclear cPLA₂- than contact-inhibited confluent or serum-starved cells. The broad-range protein kinase inhibitor staurosporine caused a decrease in the nuclear level of cPLA₂-, whereas the protein phosphatase inhibitor okadaic acid increased the level of nuclear cPLA₂-. Using inhibitors for specific mitogen-activated protein (MAP) kinases, both p42/44^MAPK and p38^MAPK were shown to be important in modulating nuclear localisation. Finally, inhibition of nuclear import and export using Agaricus bisporus lectin and leptomycin B, respectively, demonstrated that cPLA₂- contains functional nuclear localisation and export signals. Thus we have identified a novel mode of regulation of cPLA₂-. This, together with the increasing body of evidence supporting the role of nuclear lipid second messengers in gene expression and proliferation, may have important implications for controlling the growth of endothelial cells in angiogenesis and tumour progression.

Key words: Nucleus, Endothelial, EA.hy.926, Cytosolic phospholipase A₂-

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