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Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene
Christina EL Naaman1, Birgitte Grum-Schwensen, Ahmed Mansouri
1Department of Molecular Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK2100 Copenhagen, Denmark.
Abstract:
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.
Insights
Mice lacking the S100A4 gene developed spontaneous tumors and showed reduced apoptosis. This suggests S100A4 protein is crucial for p53 tumor suppressor function, preventing cancer development.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- The S100A4 protein, a calcium-binding protein, is implicated in promoting metastasis.
- The S100A4 gene's role in tumor suppression and its interaction with p53 are not fully understood.
Purpose of the Study:
- To investigate the in vivo function of S100A4 in tumor suppression.
- To determine the impact of S100A4 deficiency on p53-mediated apoptosis and tumor development.
Main Methods:
- Generation of a germ-line S100A4-inactivated mouse model (S100A4-/-).
- Observation of tumor development, sex ratios, and apoptosis frequency in S100A4-/- mice.
- Assessment of p53 target gene activation (waf/p21/cip1, bax) post-irradiation.
Main Results:
- S100A4-/- mice exhibited an abnormal sex ratio, suggesting embryonic lethality.
- 10% of aged S100A4-/- mice developed spontaneous, p53-positive tumors.
- Apoptosis frequency and p53 target gene activation were reduced in S100A4-/- mice after irradiation.
Conclusions:
- S100A4 deficiency leads to functional destabilization of the p53 tumor suppressor.
- S100A4 plays a critical role in p53-mediated apoptosis and tumor suppression.
- The S100A4-p53 interaction is essential for preventing spontaneous tumor formation.
