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Degradation of the extracellular matrix is part of the
pathological process associated with many diseases: e.g., joint destruction in arthritis, invasion
and metastasis in cancer, bone dissolution in periodontitis, and plaque
rupture in athererosclerosis. Most of this connective tissue degradation is
accomplished by a family of enzymes called the Matrix Metalloproteinases, or
MMPs, a family of enzymes that, collectively, degrade most matrix
components. A sub-family of MMPs is
the interstitial collagenases, enzymes that specifically degrade the stromal
collagens, types I, II and III. Since
these collagens are the most abundant protein in our body, the collagenases
have a major role in connective tissue modeling and remodeling. Of the three interstitial collagenases, MMP-1
(collagenase-1) is the most ubiquitously expressed. It is produced by a wide variety of normal
cells, e.g., stromal fibroblasts, macrophages, endothelial cells, and
epithelial cells, as well as by numerous tumors, suggesting a broad-based
role for this collagenase in tumor biology.
Normally, expression of MMP-1 by most cells is low, but is readily
induced by phorbol esters, growth factors and inflammatory cytokines. In contrast, some tumors display
constitutively high levels of MMP-1 expression, even in the absence of
apparent external stimuli. A genetic variation in the MMP-1 promoter can influence
the level of MMP-1 transcription, and hence, the potential of this gene to
mediate connective tissue degradation.
This variation is a single nucleotide polymorphism (SNP) located at
–1607 bp, where an insertion of a guanine base (G) creates the
sequence, 5'-GGAT-3', the core binding site for members of the Ets family of
transcription factors. We have
demonstrated that the 2G DNA displays heightened MMP-1 transcription in both
tumor cells and in normal fibroblasts, and the levels of MMP-1 expression may
result from the presence of the 2G allele and from elevated expression of the
transcription factors that bind to this site. This SNP in the MMP-1 promoter is not a rare mutation or
genetic variation found in a few tumor cells. Genotyping of 100 normal
individuals indicated that the distribution of this SNP in the normal
population is approximately: 30% = 1G homozygous; 30% = 2G homozygous; 40% =
1G/2G heterozygous. However, in tumor
cells cultured in vitro, the
incidence of the 2G allele rises to 62% (P = < 0.001), supporting the
hypothesis that it correlates with aggressive tumors. This in
vitro correlation has been confirmed in
vivo, where patients with ovarian
cancer had a significantly higher incidence of the 2G allele, compared to
non-cancer controls, and expressed higher levels of MMP-1 protein. The hypothesis is, therefore, that heightened MMP-1
expression results from the presence of (a) the 2G allele and (b) the
appropriate transcription factors that bind to this site. In the absence of these factors, MMP-1
expression from the 2G allele is not necessarily increased compared to the 1G
allele. The precise identity of the
Ets family member(s) binding to this site is not known, and it is possible
that several Ets proteins can function to drive transcription. Once the identity of these proteins is
determined, they may become a target for therapeutic intervention to reduce
MMP-1 expression in certain diseases. Given the strong link between increased MMP-1 expression
and the presence of the 2G allele, it is possible that a simple genetic
analysis of this polymorphism may provide a useful and potentially important
mechanism for predicting prognosis in certain diseases, such as cancer,
arthritis, cardiovascular disease, and periodontitis. Inhibiting MMP-1
synthesis represents a new therapeutic approach of molecular medicine for the
21st century. This technology is claimed in
the issued United States Patent Nos. 7,033,756 and 7,473,774.
We are seeking an industrial partner interested in its
commercialization. (Ref: J17) |
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«Technology Transfer Office : Sponsored Projects : Dartmouth College |
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Phone: (603) 646-3027 |
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Fax: (603) 646-3670 |
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