Inhibition of the putative tumor suppressor gene TIMP-3 by tumor-derived p53 mutants and wild type p53

The p53 gene is a tumor suppressor that regulates the expression of genes required for cell cycle arrest or apoptosis. Mutations in p53 have been observed in over 60% of all human cancers. Certain classes of mutant p53 proteins maintain some of their activities or acquire novel activities and thus may contribute to the transformed phenotype. By carrying out an analysis of differential gene expression using cDNA expression arrays, we compared the expression patterns of cells expressing no p53 to isogenic lines expressing the codon 248 Arg to Trp mutant p53 allele (R248W). In this report, we show that the R248W and D281G p53 mutants, two of the more commonly occurring mutations, as well as wild type p53, repress transcription of the tissue inhibitor of metalloproteinases type 3 (TIMP3) gene by greater than tenfold. TIMP3 expression has been observed to be repressed in many tumors and its reduced expression is thought to contribute to tumor metastasis and invasiveness by allowing increased activity of metalloproteinases in the extracellular matrix. Since mutant forms of p53 tend to be expressed at greatly elevated levels in many human tumors, the retention of their ability to repress TIMP3 illustrate one mechanism by which mutant forms of the p53 gene may contribute to tumorigenesis.