The increase of cell-membranous phosphatidylcholines containing polyunsaturated fatty acid residues induces phosphorylation of p53 through activation of ATR

Abstract

The G1 phase of the cell cycle is marked by the rapid turnover of phospholipids. This turnover is regulated by CTP:phosphocholine-cytidylyltransferase (CCT) and group VIA Ca2+-independent-phospholipase A2 (iPLA2). We previously reported that inhibition of iPLA2 arrests cells in G1 phase of the cell cycle by activating the p53-p21 checkpoint. Here we further characterize the mechanism of p53 activation. We show that specific inhibition of iPLA2 induces a time dependent phosphorylation of Ser15 in p53 in the absence of DNA damage. This phosphorylation requires the kinase ataxia-telangiectasia and Rad-3-related (ATR) but not the ataxia-telangiectasia-mutated (ATM) kinase. Moreover, we identify in cell membranes a significant increase of phosphatidylcholines (PCs) containing chains of polyunsaturated fatty acids and a decrease of PCs containing saturated fatty acids in response to inhibition of iPLA2. The time course of phosphorylation of Ser15 in p53 correlates with increasing levels of PCs containing polyunsaturated fatty acids. We further demonstrate that the PCs with linoleic acid in their sn-2 position (18:2n6) induce phosphorylation of Ser15 in p53 in an ATR-dependent manner. Our findings establish that cells can regulate the levels of polyunsaturated fatty acids in phospholipids through iPLA2-mediated deacylation of PCs. Disruption of this regulation increases the proportions of PCs containing polyunsaturated fatty acids and activates the ATR-p53 signalling pathway.

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

“…The ability of iPLA 2 ␤ to promote cell proliferation becomes prominent in the context of tumorigenesis. Several in vitro studies reveal higher expression of iPLA 2 ␤ in stimulated immortal cell lines and that chemical inhibition or siRNAs targeted against iPLA 2 ␤ reduces proliferation and promotes apoptosis of the cells ( 97, 108,125,[356][357][358][359][360][361][362][363][364]. Subsequent studies targeting specifi c cancers suggest that iPLA 2 ␤ promotes cancer cell growth via signal transduction pathways involving epidermal growth factor receptors, MAPKs, E3 ubiquitin-protein ligase mdm2, tumor suppressor protein p53, and cell cycle regulator p21 (365)(366)(367).…”

Cell Cycle Arrest by Hybrid Liposomes for Human Lung Carcinoma Cells

“…With respect to cell cycle regulation, some researchers have reported that cell cycle arrest was closely associated with metabolic events in plasma membranes [21,22,[26][27][28][29]. We have previously reported that HL affects the fluidity of plasma membranes [30], cellular lipid constituents [31][32][33][34][35][36][37] and lipid microdomain (lipid rafts [30] or caveolae structures [31]) in cancer cells, and trigger the growth-inhibition or apoptosis. Although the mechanistic details are not yet clear, it seems that HL could accumulate in plasma membranes of NSCLC cells [13], change the membrane characteristics related to cell cycle progression, and induce G 0 /G 1 phase arrest or apoptosis.…”

Cellular Responses to Tritium Exposure in Rainbow Trout: Hto- And Obt-Spiked Feed Exposure Experiments

“…The data do not exclude a connection between irradiation and an induced turnover of phospholipids that influence cell signaling. It is known that PUFA levels in membrane lipids correlate with p53 levels [29,30] and also that gamma irradiation is connected with p53 induction and the apoptotic response. However, to date, no systematic research has been performed on membrane lipid remodelling due to irradiation conditions and the related membrane signalling.…”