title: Distal interleukin-1β (IL-1β) response element of human matrix metalloproteinase-13 (MMP-13) binds activator protein 1 (AP-1) transcription factors and regulates gene expression.
abstract: The collagenase matrix metalloproteinase-13 (MMP-13) plays an important role in the destruction of cartilage in arthritic joints. MMP-13 expression is strongly up-regulated in arthritis, largely because of stimulation by inflammatory cytokines such as IL-1β. Treatment of chondrocytes with IL-1β induces transcription of MMP-13 in vitro. IL-1β signaling converges upon the activator protein-1 transcription factors, which have been shown to be required for IL-1β-induced MMP-13 gene expression. Using chromatin immunoprecipitation (ChIP), we detected activator protein-1 binding within an evolutionarily conserved DNA sequence ∼20 kb 5' relative to the MMP-13 transcription start site (TSS). Also using ChIP, we detected histone modifications and binding of RNA polymerase II within this conserved region, all of which are consistent with transcriptional activation. Chromosome conformation capture indicates that chromosome looping brings this region in close proximity with the MMP-13 TSS. Finally, a luciferase reporter construct driven by a component of the conserved region demonstrated an expression pattern similar to that of endogenous MMP-13. These data suggest that a conserved region at 20 kb upstream from the MMP-13 TSS includes a distal transcriptional response element of MMP-13, which contributes to MMP-13 gene expression.
authors.affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Schmucker
authors.forename: Jason B
authors.initials: JB
authors.lastname: Wright
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cole
authors.forename: Constance E
authors.initials: CE
authors.lastname: Brinckerhoff
mesh_terms: D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; C508585:IL1B protein, human; D053583:Interleukin-1beta; D018808:Transcription Factor AP-1; D012319:RNA Polymerase II; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13
references.citation: Nature. 2007 Jun 14;447(7146):799-816
references.pmid: 17571346
references.citation: Arthritis Res Ther. 2008;10(6):R139
references.pmid: 19046432
references.citation: Arthritis Rheum. 2000 Oct;43(10):2189-201
references.pmid: 11037878
references.citation: Genome Res. 2004 Apr;14(4):708-15
references.pmid: 15060014
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: Mod Rheumatol. 2004;14(3):197-204
references.pmid: 17143675
references.citation: Nat Genet. 2007 Mar;39(3):311-8
references.pmid: 17277777
references.citation: J Clin Invest. 1996 Feb 1;97(3):761-8
references.pmid: 8609233
references.citation: Mol Biosyst. 2008 Nov;4(11):1046-57
references.pmid: 18931780
references.citation: Biochim Biophys Acta. 2009 Jan;1789(1):17-25
references.pmid: 18675948
references.citation: Mol Cell Biol. 2003 Mar;23(5):1808-16
references.pmid: 12588998
references.citation: Arthritis Rheum. 2000 Apr;43(4):801-11
references.pmid: 10765924
references.citation: Biochem J. 1998 Apr 1;331 ( Pt 1):341-6
references.pmid: 9512498
references.citation: Mol Cell. 2002 Dec;10(6):1453-65
references.pmid: 12504019
references.citation: Biochem J. 1997 Apr 1;323 ( Pt 1):13-6
references.pmid: 9173871
references.citation: Genomics. 1997 Mar 1;40(2):222-33
references.pmid: 9119388
references.citation: Arthritis Rheum. 2007 Mar;56(3):892-904
references.pmid: 17328062
references.citation: Am J Vet Res. 1996 Nov;57(11):1631-4
references.pmid: 8915443
references.citation: Wiley Interdiscip Rev Syst Biol Med. 2010 Jul-Aug;2(4):422-437
references.pmid: 20836039
references.citation: Science. 2002 Feb 15;295(5558):1306-11
references.pmid: 11847345
references.citation: Nucleic Acids Res. 2001 Nov 1;29(21):4361-72
references.pmid: 11691923
references.citation: Front Biosci. 2006 Jan 01;11:529-43
references.pmid: 16146751
references.citation: Oncogene. 2009 Dec 3;28(48):4237-48
references.pmid: 19734937