| The increase of cell-membranous phosphatidylcholines containing polyunsaturated fatty acid residues induces phosphorylation of p53 through activation of ATR. | |
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MedLine Citation:
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PMID: 18032786 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 Ca(2+)-independent-phospholipase A(2) (iPLA(2)). We previously reported that inhibition of iPLA(2) 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 iPLA(2) 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 iPLA(2). 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 iPLA(2)-mediated deacylation of PCs. Disruption of this regulation increases the proportions of PCs containing polyunsaturated fatty acids and activates the ATR-p53 signalling pathway. |
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Authors:
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Xu Hannah Zhang; Chunying Zhao; Zhongmin Alex Ma |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of cell science Volume: 120 ISSN: 0021-9533 ISO Abbreviation: J. Cell. Sci. Publication Date: 2007 Dec |
Date Detail:
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Created Date: 2007-11-22 Completed Date: 2008-03-27 Revised Date: 2010-09-14 |
Medline Journal Info:
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Nlm Unique ID: 0052457 Medline TA: J Cell Sci Country: England |
Other Details:
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Languages: eng Pagination: 4134-43 Citation Subset: IM |
Affiliation:
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Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Cycle Proteins / metabolism* Cell Line Cell Line, Tumor Cell Membrane / chemistry Choline-Phosphate Cytidylyltransferase / metabolism Dose-Response Relationship, Drug Fatty Acids, Unsaturated / chemistry Group VI Phospholipases A2 / antagonists & inhibitors, genetics HCT116 Cells Humans In Situ Nick-End Labeling Insulin-Secreting Cells / metabolism Models, Biological Naphthalenes / pharmacology Osteosarcoma / pathology Phosphatidylcholines / biosynthesis*, chemistry Phosphorylation Protein-Serine-Threonine Kinases / metabolism* Pyrones / pharmacology RNA, Small Interfering / metabolism, pharmacology Rats Tumor Suppressor Protein p53 / chemistry, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK063076-01A1/DK/NIDDK NIH HHS; R01 DK063076-02/DK/NIDDK NIH HHS; R01 DK063076-03/DK/NIDDK NIH HHS; R01 DK063076-04/DK/NIDDK NIH HHS; R01 DK063076-05/DK/NIDDK NIH HHS; R01DK063076/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/Fatty Acids, Unsaturated; 0/Naphthalenes; 0/Phosphatidylcholines; 0/Pyrones; 0/RNA, Small Interfering; 0/Tumor Suppressor Protein p53; 88070-98-8/6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; EC 2.7.1.-/ATR protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.7.15/Choline-Phosphate Cytidylyltransferase; EC 3.1.1.4/Group VI Phospholipases A2 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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