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Specific Methylation Events Contribute to the Transcriptional Repression of the Mouse Tissue Inhibitor of Metalloproteinases-3 Gene in Neoplastic Cells

Gene Regulation Section, Laboratory of Biochemical Physiology, Building 560, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702

The tissue inhibitor of metalloproteinases-3 (TIMP-3) gene is specifically down-regulated in neoplastic cells of the mouse JB6 progression model, suggesting a role for TIMP-3 inactivation in neoplastic progression. On the basis of 5-azacytidine reversal, the mechanism for this down-regulation appears to involve changes in the methylation state of the TIMP-3 promoter. Although total genomic methylation levels are comparable, specific differences in the methylation of the TIMP-3 promoter were observed between preneoplastic and neoplastic JB6 cells at three HpaII sites, with preneoplastic cells being less methylated. Expression of antisense methyltransferase in a neoplastic JB6 variant known to be hypermethylated in TIMP-3 resulted in reactivation of the endogenous TIMP-3 gene and restoration of hypomethylated status to the three implicated HpaII sites. Thus, hypermethylation at specific sequences in the TIMP-3 promoter appears to contribute to the silencing of the gene in neoplastic cells.

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