NF-kappaB and ZBP-89 regulate MMP-3 expression via a polymorphic site in the promoter.
A 5T/6T polymorphism in the human MMP-3 promoter affects gene expression and impacts the risk and/or severity of various pathological conditions. Chromatin immunoprecipitation (ChIP) in human fibroblasts homozygous for the 6T site demonstrate that it is bound by NF-kappaB and ZBP-89 transcription factors in its native chromatin. ChIP in COS-1 cells transfected with plasmids containing the 5T and 6T sites in the context of 2kb of the MMP-3 promoter showed that NF-kappaB p50 binds preferentially to the 6T site, while more ZBP-89 binding is detected to the 5T site. Over-expressed ZBP-89 increased transcription from the 5T promoter but not from the 6T, while NF-kappaB decreased transcription from both promoters, even in the presence of excess ZBP-89. A model is suggested in which the physiological impact of the polymorphism is dependent on the relative levels and activities of these competing factors in various cell types and conditions.
Borghaei
Ruth C
RC
Dept. of Biochemistry and Molecular Biology, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USA. ruthb@pcom.edu
Gorski
Grzegorz
G
Javadi
Masoud
M
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D014157:Transcription Factors; C110951:ZNF148 protein, human; D019278:Matrix Metalloproteinase 3