title: A distal enhancer controls cytokine-dependent human cPLA2α gene expression.
abstract: Specific control of group IVA cytosolic phospholipase A2 (cPLA2α or PLA2G4A) expression modulates arachidonic acid production, thus tightly regulating the downstream effects of pro- and anti-inflammatory eicosanoids. The significance of this pathway in human disease is apparent in a range of pathologies from inflammation to tumorigenesis. While much of the regulation of cPLA2α has focused on posttranslational phosphorylation of the protein, studies on transcriptional regulation of this gene have focused only on proximal promoter regions. We have identified a DNase I hypersensitive site encompassing a 5' distal enhancer element containing a highly conserved consensus AP-1 site involved in transcriptional activation of cPLA2α by interleukin (IL)-1β. Chromatin immunoprecipitation (ChIP), knockdown, knockout, and overexpression analyses have shown that c-Jun acts both in a negative and positive regulatory role. Transcriptional activation of cPLA2α occurs through the phosphorylation of c-Jun in conjunction with increased association of C/EBPβ with the distal novel enhancer. The association of C/EBPβ with the transcriptional activation complex does not require an obvious DNA binding site. These data provide new and important contributions to the understanding of cPLA2α regulation at the transcriptional level, with implications for eicosanoid metabolism, cellular signaling, and disease pathogenesis.
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Justin S
authors.initials: JS
authors.lastname: Bickford
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Beachy
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Newsom
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Barilovits
authors.forename: John-David H
authors.initials: JD
authors.lastname: Herlihy
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Qiu
authors.forename: Jewell N
authors.initials: JN
authors.lastname: Walters
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Harry S
authors.initials: HS
authors.lastname: Nick
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation; D054513:Group IV Phospholipases A2 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human
keywords: CCAAT/enhancer-binding protein β; c-Jun; gene regulation; group IVA phospholipase A2
references.citation: J Cell Physiol. 2011 Aug;226(8):2103-14
references.pmid: 21520062
references.citation: Nature. 1992 Aug 13;358(6387):581-4
references.pmid: 1380129
references.citation: Nucleic Acids Res. 1994 Nov 25;22(23):5093-8
references.pmid: 7800505
references.citation: Prog Lipid Res. 2011 Apr;50(2):152-92
references.pmid: 21185866
references.citation: Carcinogenesis. 2004 Aug;25(8):1517-24
references.pmid: 15033900
references.citation: Thromb Haemost. 2006 Oct;96(4):417-22
references.pmid: 17003917
references.citation: Virology. 2006 May 10;348(2):354-69
references.pmid: 16458341
references.citation: Biochim Biophys Acta. 2004 Nov 5;1680(3):145-57
references.pmid: 15507318
references.citation: Mol Cell Biol. 2004 Oct;24(20):9006-18
references.pmid: 15456874
references.citation: Gastroenterology. 1999 Apr;116(4):855-64
references.pmid: 10092307
references.citation: Mol Cell Biol. 1999 Apr;19(4):2936-45
references.pmid: 10082561
references.citation: J Biol Chem. 2010 Apr 9;285(15):11433-44
references.pmid: 20154088
references.citation: Nature. 1997 Dec 11;390(6660):622-5
references.pmid: 9403693
references.citation: Clin Exp Immunol. 2007 Oct;150(1):124-31
references.pmid: 17672871
references.citation: Oncogene. 2000 Nov 30;19(51):5906-18
references.pmid: 11127822
references.citation: BMC Genomics. 2011 Jul 15;12:365
references.pmid: 21762485
references.citation: J Biol Chem. 2001 Nov 16;276(46):42737-43
references.pmid: 11559711
references.citation: Genes Dev. 1997 Sep 1;11(17):2153-62
references.pmid: 9303532
references.citation: Mol Cell Biol. 1986 Sep;6(9):3173-9
references.pmid: 3023965
references.citation: J Mol Endocrinol. 2008 Jul;41(1):25-34
references.pmid: 18562675
references.citation: Mol Neurobiol. 2012 Jun;45(3):596-604
references.pmid: 22648535
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1260-6
references.pmid: 16443645
references.citation: Prog Lipid Res. 2006 Nov;45(6):487-510
references.pmid: 16814865
references.citation: Bioessays. 1997 Feb;19(2):153-60
references.pmid: 9046245
references.citation: Biochem J. 2008 Mar 15;410(3):473-84
references.pmid: 18052938
references.citation: Nucleic Acids Res. 2008 Jan;36(1):217-27
references.pmid: 18025046
references.citation: Exp Cell Res. 2005 Aug 15;308(2):459-68
references.pmid: 15950217
references.citation: Cell Microbiol. 2010 Oct;12(10):1369-77
references.pmid: 20642808
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Apr;278(4):L649-57
references.pmid: 10749741
references.citation: J Hepatol. 2011 Dec;55(6):1281-90
references.pmid: 21703211
references.citation: J Biol Chem. 1990 Feb 15;265(5):2856-64
references.pmid: 2406241
references.citation: Curr Opin Pulm Med. 2000 Jan;6(1):15-20
references.pmid: 10608420
references.citation: J Biol Chem. 2001 Aug 3;276(31):29200-9
references.pmid: 11369759
references.citation: Mol Cell. 2004 Jan 30;13(2):241-50
references.pmid: 14759369
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14461-6
references.pmid: 15452344
references.citation: J Biol Chem. 2008 Sep 19;283(38):25774-85
references.pmid: 18559338
references.citation: J Lipid Res. 2001 Oct;42(10):1678-86
references.pmid: 11590225
references.citation: Arthritis Rheum. 2011 Oct;63(10):2905-17
references.pmid: 21702012
references.citation: Biochim Biophys Acta. 1994 Apr 6;1217(3):345-7
references.pmid: 8148385
references.citation: Lab Invest. 2009 Jun;89(6):695-707
references.pmid: 19333233
references.citation: J Immunol. 2001 Jun 15;166(12):7469-76
references.pmid: 11390500
references.citation: Neuroreport. 2006 Feb 27;17(3):303-7
references.pmid: 16462602
references.citation: J Biol Chem. 1997 Jun 6;272(23):14501-4
references.pmid: 9169405
references.citation: J Natl Cancer Inst. 2010 Sep 22;102(18):1377-9
references.pmid: 20729476
references.citation: J Cell Biol. 1999 Dec 27;147(7):1365-70
references.pmid: 10613894
references.citation: Proc Natl Acad Sci U S A. 2001 May 22;98(11):6198-203
references.pmid: 11371641
references.citation: Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):679-85
references.pmid: 15681294
references.citation: J Biol Chem. 2011 Oct 14;286(41):35499-35508
references.pmid: 21862584
references.citation: Cardiovasc Drugs Ther. 2009 Feb;23(1):49-59
references.pmid: 18931897
references.citation: Cancer Res. 2002 May 1;62(9):2522-30
references.pmid: 11980644
references.citation: EMBO J. 1992 Dec;11(13):4917-22
references.pmid: 1334462
references.citation: Biochem J. 2005 Apr 1;387(Pt 1):239-46
references.pmid: 15540987
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Lipid Res. 2009 Apr;50 Suppl:S237-42
references.pmid: 19011112
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7276-81
references.pmid: 10377405
references.citation: Biochem J. 2012 Apr 15;443(2):561-71
references.pmid: 22260630
references.citation: J Clin Invest. 1994 Feb;93(2):571-7
references.pmid: 8113394
references.citation: J Biol Chem. 2001 Jan 12;276(2):1226-32
references.pmid: 11042196
references.citation: Mol Cell Biol. 2007 Mar;27(6):2155-65
references.pmid: 17220277
references.citation: Gut. 1995 Sep;37(3):380-5
references.pmid: 7590434
references.citation: Cell. 2000 Oct 13;103(2):239-52
references.pmid: 11057897
references.citation: Mol Cell. 2009 Jul 10;35(1):48-57
references.pmid: 19595715
references.citation: Arthritis Rheum. 1994 May;37(5):653-61
references.pmid: 8185692
references.citation: EMBO J. 2003 Feb 17;22(4):882-92
references.pmid: 12574124
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Mar;280(3):L390-9
references.pmid: 11159021
references.citation: J Mol Cell Cardiol. 2007 Oct;43(4):465-78
references.pmid: 17720185
references.citation: Am J Respir Cell Mol Biol. 2011 Aug;45(2):436-44
references.pmid: 21148742
references.citation: J Biol Chem. 2007 May 4;282(18):13290-302
references.pmid: 17344216
references.citation: J Biol Chem. 1999 Feb 5;274(6):3345-54
references.pmid: 9920876
references.citation: Cell. 1998 May 15;93(4):531-41
references.pmid: 9604929
references.citation: Nat Immunol. 2000 Jul;1(1):42-6
references.pmid: 10881173
references.citation: Arthritis Rheum. 2012 Jul;64(7):2114-25
references.pmid: 22231145