Mini reviewPolymorphism in matrix metalloproteinase gene promoters: implication in regulation of gene expression and susceptibility of various diseases
Introduction
At least 20 human matrix metalloproteinases (MMPs) have been identified (Table 1). In vitro studies have shown that the MMPs are capable of degrading a range of connective tissue proteins, indicating that these enzymes may play a role in connective tissue destruction and remodelling associated with various pathological processes, such as cancer invasion and metastasis, cartilage destruction in arthritis, atherosclerotic plaque rupture, and the development of aneurysms (Birkedal-Hansen et al., 1993, Murphy and Reynolds, 1993, Nagase and Woessner, 1999). Until recently, direct evidence has mostly come from ex vivo studies in which enhanced expression of MMPs can be detected in diseased tissues using RNA and protein analysis techniques such as in situ hybridisation, reverse transcriptase PCR, immunohistochemistry and zymography (Woessner, 1998). Over the last few years, however, other lines of evidence have also been accumulating. First, increased plasma/serum levels of certain MMPs have been reported in patients with cancer (Jung et al., 1997, Torii et al., 1997, Iizasa et al., 1999, Lein et al., 2000), rheumatoid arthritis (Zucker et al., 1994), osteoarthritis (Naito et al., 1999), systemic lupus erythematosus (Zucker et al., 1999a), multiple sclerosis (Lichtinghagen et al., 1999), polycystic kidney disease (Nakamura et al., 2000), abdominal aortic aneurysm (McMillan and Pearce, 1999), unstable angina (Kai et al., 1998) or acute myocardial infarction (Kai et al., 1998), likely due to seeping of MMP proteins from diseased tissues into the blood circulation (Zucker et al., 1999b). Second, studies of transgenic and gene knock-out animal models have demonstrated in vivo that MMP-3 can promote tumorigenesis (Sternlicht et al., 1999), and that MMP-3 as well as MMP-1 are involved in the process of dermal wound healing (Di Colandrea et al., 1998, Bullard et al., 1999).
Third, a number of naturally occurring variants of human MMP genes have been identified and found to be associated with susceptibility and/or progression of atherosclerosis, aneurysms and cancers, which is the subject of this brief overview.
Section snippets
Regulation of MMP expression and promoters of MMP genes
There are a number of regulatory mechanisms that can influence the ultimate impact of an MMP on extracellular matrix degradation. These at least include the following three most intensely studied mechanisms: regulation of transcription, activation of latent MMPs, and inhibition of MMP activity by tissue inhibitors of metalloproteinases (TIMPs). It appears, however, that for most MMPs, the key step is transcriptional regulation, because most MMP genes are expressed only when active physiological
Sequence variations in the human genome and their implications in disease susceptibility
DNA polymorphisms [naturally occurring DNA sequence changes with more than one variant (allele) having a frequency greater than 1% in a human population] have been estimated to occur on the average at one in every 1000 base pairs throughout the human genome (Sherry et al., 1999). Approximately 90% of DNA polymorphisms are single nucleotide polymorphisms (SNPs) due to single base substitutions (Collins et al., 1998). Some SNPs result in the generation or removal of a restriction endonuclease
Polymorphism in the MMP-3 (stromelysin-1) gene promoter
A polymorphism in the promoter of the MMP-3 gene was first reported in 1995 (Ye et al., 1995). The polymorphism is due to variation in the length of a polymonomeric track of adenosines located from position −1612 relative to the transcription start site, resulting in one allele having five adenosines (5A) and the other allele having six adenosines (6A). In vitro promoter functional analyses showed that the 5A allele had greater promoter activities as compared with the 6A allele in fibroblasts
Polymorphisms in the MMP-9 (gelatinase B) gene promoter
A number of polymorphisms in the MMP-9 gene have been reported (St Jean et al., 1995, Zhang et al., 1999a), and two of them in the promoter of this gene have been shown to be functionally important. These are a (CA)n microsatellite polymorphism at position from −90 and a single nucleotide polymorphism at position −1562 (Peters et al., 1999, Shimajiri et al., 1999, Zhang et al., 1999b).
The multi-allelic microsatellite polymorphism has a bi-model distribution of allele frequencies, with the first
Polymorphism in the MMP-1 (collagenase-1) gene promoter
A polymorphism resulting from an insertion/deletion of a guanosine at position −1607 has been identified in the promoter of the MMP-1 gene (Rutter et al., 1998). Two alleles have been detected, one allele having a single gaunosine (1G) and the other having two guanosines (2G) at the polymorphic site. Promoter assays have indicated that this is also a functional polymorphism. The two guanosines (at positions −1607 and −1608) together with an adjacent adenosine create a core binding site
Polymorphism in the MMP-12 (metalloelastase) gene promoter
As discussed above, the cis-element AP-1 located at approximately 70 bp upstream from the transcriptional start site in a number of MMP genes plays a vital role in transcriptional regulation. Recently, a polymorphism was identified immediately adjacent to this AP-1 site in the MMP-12 gene (Jormsjo et al., 2000). The polymorphism, located at position −82, is due to an A to G substitution, with the A allele being more prevalent. In vitro studies have shown that this sequence change has an effect
Acknowledgements
The author would like to thank Professors Gillian Murphy and Dylan Edwards and Dr Ian Clark who kindly read this manuscript and provided valuable comments. Current research of the author is supported by the British Heart Foundation (PG/98183 and PG/98192).
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