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[Cancer Research 58, 5321-5325, December 1, 1998]
© 1998 American Association for Cancer Research
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A Single Nucleotide Polymorphism in the Matrix Metalloproteinase-1 Promoter Creates an Ets Binding Site and Augments Transcription1

Joni L. Rutter, Teresa I. Mitchell, Giovanna Butticè, Jennifer Meyers, James F. Gusella, Laurie J. Ozelius and Constance E. Brinckerhoff2

Departments of Pharmacology and Toxicology [J. L. R.], Biochemistry [T. I. M., J. M., C. E. B.], and Medicine [C. E. B.], Dartmouth Medical School, Hanover, New Hampshire 03755; Institute de Biologie de Lille, Lille, France 59021 [G. B.]; and Molecular Neurogenetics Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 [J. F. G., L. J. O.].

Matrix metalloproteinases (MMPs) facilitate cellular invasion by degrading the extracellular matrix, and their regulation is partially dependent on transcription. Binding sites for members of the Ets family of transcription factors are present within MMP promoters and are potent positive regulators. We report a single nucleotide polymorphism at -1607 bp in the MMP-1 promoter, where an additional guanine (G) creates an Ets binding site, 5'-GGA-3'. This polymorphism displays significantly higher transcription in normal fibroblasts and in melanoma cells than the 1 G polymorphism, and it binds substantially more nuclear extract and recombinant ETS-1. Analysis of control DNAs from the Center d'Etude du Polymorphisme Humain pedigrees reveals that this polymorphism is not a mutation, with a frequency of the 2 G polymorphism at 30%. In contrast, in eight tumor cell lines, this frequency increased to 62.5% (P < 0.0001). Thus, this MMP-1 polymorphism contributes to increased transcription, and cells expressing the 2 G polymorphism may provide a mechanism for more aggressive matrix degradation, thereby facilitating cancer progression.

1 Supported by NIH Grants AR-26599 (to C. E. B.) and NS-24279 (to J. F. G.), Grant ST32-CA09658 (to J. L. R.) from the National Cancer Institute, and a grant from the Ronya and Gregory Kozmetsky Foundation (to C. E. B.).

2 To whom requests for reprints should be addressed, at Department of Medicine and Biochemistry, Dartmouth Medical School, Hanover, NH 03755, Phone: (603) 650-1609; Fax: (603) 650-1128; E-mail: c.e.brinckerhoff@dartmouth.edu.

Received 8/27/98. Accepted 10/19/98.




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A Naturally Occurring Sequence Variation That Creates a YY1 Element Is Associated with Increased Cystic Fibrosis Transmembrane Conductance Regulator Gene Expression
J. Biol. Chem., February 4, 2000; 275(5): 3561 - 3567.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
Y. Kanamori, M. Matsushima, T. Minaguchi, K. Kobayashi, S. Sagae, R. Kudo, N. Terakawa, and Y. Nakamura
Correlation between Expression of the Matrix Metalloproteinase-1 Gene in Ovarian Cancers and an Insertion/Deletion Polymorphism in Its Promoter Region
Cancer Res., September 1, 1999; 59(17): 4225 - 4227.
[Abstract] [Full Text] [PDF]

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A. C. Ranganathan, K. K. Nelson, A. M. Rodriguez, K.-H. Kim, G. B. Tower, J. L. Rutter, C. E. Brinckerhoff, T.-T. Huang, C. J. Epstein, J. J. Jeffrey, et al.
Manganese Superoxide Dismutase Signals Matrix Metalloproteinase Expression via H2O2-dependent ERK1/2 Activation
J. Biol. Chem., April 20, 2001; 276(17): 14264 - 14270.
[Abstract] [Full Text] [PDF]


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