Tumor suppressor p53 protein is a new target for the metastasis-associatedMts1/S100A4 protein - Functional consequences of their interaction

A physical and functional interaction between the Ca2+-binding protein Mts1 (S100A4) and the tumor suppressor p53 protein is shown here for the first time. We demonstrate that Mts1 binds to the extreme end of the C-terminal r egulatory domain of p53 by several in vitro and in vivo approaches: co-immu noprecipitation, affinity chromatography, and far Western blot analysis. Th e Mts1 protein in vitro inhibits phosphorylation of the full-length p53 and its C-terminal peptide by protein kinase C but not by casein kinase II. Th e Mts1 binding to p53 interferes with the DNA binding activity of p53 in vi tro and reporter gene transactivation in, vivo, and this has a regulatory f unction. A differential modulation of the p53 target gene (p21/WAF: box, th rombospondin-l, and mdm-2) transcription was observed upon Mts1 induction i n tet-inducible cell lines expressing wild type p53. Mts1 cooperates with w ild type p53 in apoptosis induction. Our data imply that the ability of Mts 1 to enhance p53 dependent apoptosis might accelerate the loss of wild type p53 function in tumors, In this way, Mts1 can contribute to the developmen t of a more aggressive phenotype during tumor progression.