Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene
Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene
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DOI：
10.1038/sj.onc.1207420
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发表时间：
2004-04-29
期刊：
影响因子：
8
通讯作者：
Ambartsumian, N
中科院分区：
文献类型：
--
作者：
EL Naaman, C;Grum-Schwensen, B;Ambartsumian, N
促转移蛋白Mts1(S100A4)属于钙离子结合蛋白S100家族。产生了一个S100A4基因种系失活的小鼠品系。这些小鼠是存活的，在出生后没有表现出发育异常。然而，在S100A4-/-基因型的小鼠中观察到了异常的性别比，这增加了该菌株具有一定水平的胚胎致死性的可能性。总体而言，10-14个月大的S100A4缺失动物中有10%患上了肿瘤。这是肿瘤抑制基因失活的小鼠品系的一个特征。S100A4-/-小鼠自发性肿瘤均为P53阳性。最近，我们发现S100A4与P53抑癌蛋白相互作用并诱导细胞凋亡。我们认为，这种相互作用的障碍可能会影响P53的促凋亡功能，而P53参与了它的肿瘤抑制活性。S100A4-/-动物全身伽玛射线照射后，脾细胞凋亡率较野生型动物降低。P53靶基因WAF/p21/cip1和Bax的转录激活也是如此。综上所述，这些观察结果表明，S100A4-/-小鼠的自发性肿瘤是P53肿瘤抑制基因功能不稳定的结果。
Metastasis-promoting Mts1(S100A4) protein belongs to the S100 family of Ca2+-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.