Allele-specific regulation of matrix metalloproteinase-3 gene by transcription factor NF?B
Allele-specific regulation of matrix metalloproteinase-3 gene by transcription factor NF?B
Background: matrix metalloproteinase-3 (MMP3) is implicated in the pathogenesis and progression of atherosclerotic lesions. Previous studies suggested that MMP3 expression is influenced by a polymorphism (known as the 5A/6A polymorphism) in the promoter of the MMP3 gene and that this polymorphism is located within a cis-element that interacts with the transcription factor NF?B. In the present study, we sought to investigate whether MMP3 and NF?B were co-localized in atherosclerotic lesions and whether NF?B had differential effects on the two alleles of the MMP3 5A/6A polymorphism.
Methodology/Principal Findings: immunohistochemical examination showed that MMP3 and both the NF?B p50 and p65 subunits were expressed abundantly in macrophages in atherosclerotic lesions and that MMP3 expression was co-localized with p50 and p65. Chromatin immunoprecipitation experiments showed interaction of p50 and p65 with the MMP3 promoter in macrophages, with greater binding to the 5A allele than to the 6A allele. Reporter gene assays in transiently transfected macrophages showed that the 5A allele had greater transcriptional activity than the 6A allele, and that this allele-specific effect was augmented when the cells were treated with the NF?B activator lipopolysaccharides or co-transfected with p50 and/or p65 expressing plasmids, but was reduced when the cells were treated with the NF?B inhibitor 6-Amino-4-(4-phenoxyphenylethylamino)-qu?inazoline or transfected with a dominant negative mutant of IkB kinase-?.
Conclusion: these results corroborate an effect of the 5A/6A polymorphism on MMP3 transcription and indicate that NF?B has differential effects on the 5A and 6A alleles.
e9902
Souslova, Veronika
57f18600-19cf-446b-b32a-71f635c53683
Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Mann, Jelena
23defaa6-4d36-4d53-909c-f1375ee73df8
van der Loos, Chris M.
b4f9df1f-b489-4b64-9125-1c88641b6ae9
Motterle, Anna
d40cdfd5-322e-4d46-ab71-b8cb45732d84
D'Acquisto, Fulvio
a0d7b69f-116b-45a3-afbe-56645872ea31
Mann, Derek A.
7a0eb3d7-c2ca-432f-82a0-f4b0df08755d
Ye, Shu
132b6474-1927-4f93-80db-2c620a31c1ab
Toland, Amanda Ewart
edbfce4b-35a4-461c-8b4f-b7f8d5497ec8
25 March 2010
Souslova, Veronika
57f18600-19cf-446b-b32a-71f635c53683
Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Mann, Jelena
23defaa6-4d36-4d53-909c-f1375ee73df8
van der Loos, Chris M.
b4f9df1f-b489-4b64-9125-1c88641b6ae9
Motterle, Anna
d40cdfd5-322e-4d46-ab71-b8cb45732d84
D'Acquisto, Fulvio
a0d7b69f-116b-45a3-afbe-56645872ea31
Mann, Derek A.
7a0eb3d7-c2ca-432f-82a0-f4b0df08755d
Ye, Shu
132b6474-1927-4f93-80db-2c620a31c1ab
Toland, Amanda Ewart
edbfce4b-35a4-461c-8b4f-b7f8d5497ec8
Souslova, Veronika, Townsend, Paul A., Mann, Jelena, van der Loos, Chris M., Motterle, Anna, D'Acquisto, Fulvio, Mann, Derek A., Ye, Shu and Toland, Amanda Ewart
(2010)
Allele-specific regulation of matrix metalloproteinase-3 gene by transcription factor NF?B.
PLoS ONE, 5 (3), .
(doi:10.1371/journal.pone.0009902).
(PMID:20360864)
Abstract
Background: matrix metalloproteinase-3 (MMP3) is implicated in the pathogenesis and progression of atherosclerotic lesions. Previous studies suggested that MMP3 expression is influenced by a polymorphism (known as the 5A/6A polymorphism) in the promoter of the MMP3 gene and that this polymorphism is located within a cis-element that interacts with the transcription factor NF?B. In the present study, we sought to investigate whether MMP3 and NF?B were co-localized in atherosclerotic lesions and whether NF?B had differential effects on the two alleles of the MMP3 5A/6A polymorphism.
Methodology/Principal Findings: immunohistochemical examination showed that MMP3 and both the NF?B p50 and p65 subunits were expressed abundantly in macrophages in atherosclerotic lesions and that MMP3 expression was co-localized with p50 and p65. Chromatin immunoprecipitation experiments showed interaction of p50 and p65 with the MMP3 promoter in macrophages, with greater binding to the 5A allele than to the 6A allele. Reporter gene assays in transiently transfected macrophages showed that the 5A allele had greater transcriptional activity than the 6A allele, and that this allele-specific effect was augmented when the cells were treated with the NF?B activator lipopolysaccharides or co-transfected with p50 and/or p65 expressing plasmids, but was reduced when the cells were treated with the NF?B inhibitor 6-Amino-4-(4-phenoxyphenylethylamino)-qu?inazoline or transfected with a dominant negative mutant of IkB kinase-?.
Conclusion: these results corroborate an effect of the 5A/6A polymorphism on MMP3 transcription and indicate that NF?B has differential effects on the 5A and 6A alleles.
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Published date: 25 March 2010
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Local EPrints ID: 143609
URI: http://eprints.soton.ac.uk/id/eprint/143609
ISSN: 1932-6203
PURE UUID: faf312df-34ed-4307-a468-e7de9b702315
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Date deposited: 12 Apr 2010 13:07
Last modified: 14 Mar 2024 00:43
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Author:
Veronika Souslova
Author:
Paul A. Townsend
Author:
Jelena Mann
Author:
Chris M. van der Loos
Author:
Anna Motterle
Author:
Fulvio D'Acquisto
Author:
Derek A. Mann
Author:
Shu Ye
Author:
Amanda Ewart Toland
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