PMID- 20360864
OWN - NLM
STAT- MEDLINE
DCOM- 20110111
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 3
DP  - 2010 Mar 25
TI  - Allele-specific regulation of matrix metalloproteinase-3 gene by transcription 
      factor NFkappaB.
PG  - e9902
LID - 10.1371/journal.pone.0009902 [doi]
LID - e9902
AB  - 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 NFkappaB. In the present 
      study, we sought to investigate whether MMP3 and NFkappaB were co-localized in 
      atherosclerotic lesions and whether NFkappaB had differential effects on the two 
      alleles of the MMP3 5A/6A polymorphism. METHODOLOGY/PRINCIPAL FINDINGS: 
      Immunohistochemical examination showed that MMP3 and both the NFkappaB 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 
      NFkappaB activator lipopolysaccharides or co-transfected with p50 and/or p65 
      expressing plasmids, but was reduced when the cells were treated with the 
      NFkappaB inhibitor 6-Amino-4-(4-phenoxyphenylethylamino)-quinazoline or 
      transfected with a dominant negative mutant of IkB kinase-beta. CONCLUSION: These 
      results corroborate an effect of the 5A/6A polymorphism on MMP3 transcription and 
      indicate that NFkappaB has differential effects on the 5A and 6A alleles.
FAU - Souslova, Veronika
AU  - Souslova V
AD  - William Harvey Research Institute, Barts and The London School of Medicine and 
      Dentistry, Queen Mary University of London, London, United Kingdom.
FAU - Townsend, Paul A
AU  - Townsend PA
FAU - Mann, Jelena
AU  - Mann J
FAU - van der Loos, Chris M
AU  - van der Loos CM
FAU - Motterle, Anna
AU  - Motterle A
FAU - D'Acquisto, Fulvio
AU  - D'Acquisto F
FAU - Mann, Derek A
AU  - Mann DA
FAU - Ye, Shu
AU  - Ye S
LA  - eng
GR  - FS/07/021/British Heart Foundation/United Kingdom
GR  - PG/08/051/25141/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100325
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Quinazolines)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - *Alleles
MH  - Animals
MH  - Atherosclerosis/pathology
MH  - *Gene Expression Regulation, Enzymologic
MH  - Genes, Dominant
MH  - Humans
MH  - Immunohistochemistry/methods
MH  - Lipopolysaccharides/metabolism
MH  - Matrix Metalloproteinase 3/*genetics
MH  - Mice
MH  - Mutation
MH  - NF-kappa B/*metabolism
MH  - Polymorphism, Genetic
MH  - Promoter Regions, Genetic
MH  - Quinazolines/pharmacology
PMC - PMC2845631
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/04/03 06:00
MHDA- 2011/01/12 06:00
PMCR- 2010/03/25
CRDT- 2010/04/03 06:00
PHST- 2009/10/02 00:00 [received]
PHST- 2010/03/05 00:00 [accepted]
PHST- 2010/04/03 06:00 [entrez]
PHST- 2010/04/03 06:00 [pubmed]
PHST- 2011/01/12 06:00 [medline]
PHST- 2010/03/25 00:00 [pmc-release]
AID - 09-PONE-RA-13318R3 [pii]
AID - 10.1371/journal.pone.0009902 [doi]
PST - epublish
SO  - PLoS One. 2010 Mar 25;5(3):e9902. doi: 10.1371/journal.pone.0009902.