Metastasis-promoting Mts1(S100A4) protein belongs to the S100 family of Ca(2+)-binding proteins. A mouse strain with a germ-line inactivation of the S100A4 gene was generated. The mice were viable and did not display developmental abnormalities in the postnatal period. However, an abnormal sex ratio was observed in the litters with the S100A4-/- genotype, raising the possibility of a certain level of embryonic lethality in this strain. In all, 10% of 10-14-month-old S100A4-null animals developed tumors. This is a characteristic feature of mouse strains with inactivated tumor suppressor genes. Spontaneous tumors of S100A4-/- mice were p53 positive. Recently, we have shown that S100A4 interacts with p53 tumor suppressor protein and induces apoptosis. We proposed that impairment of this interaction could affect the apoptosis-promoting function of p53 that is involved in its tumor suppressor activity. The frequency of apoptosis in the spleen of S100A4-/- animals after whole-body gamma-irradiation was reduced compared to the wild-type animals. The same was true for the transcriptional activation of the p53 target genes - waf/p21/cip1 and bax. Taken together, these observations indicate that spontaneous tumors in S100A4-/- mice are a result of functional destabilization of p53 tumor suppressor gene.