Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation
Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation
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DOI：
10.1038/ng1297-423
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发表时间：
1997-12-01
期刊：
影响因子：
30.8
通讯作者：
Ashworth, A
中科院分区：
文献类型：
--
作者：
Connor, F;Bertwistle, D;Ashworth, A
BRCA 2基因的生殖系突变具有患乳腺癌的高风险。为了研究该基因的功能，我们在小鼠中产生了Brca 2突变，与Brca 2基因中的其他突变不同，当纯合子时，这些突变在胚胎发生早期是致命的，我们的一些纯合子突变小鼠存活到成年。这些动物具有广泛的缺陷，包括体积小、组织分化不当、缺乏生殖细胞和发展致命的胸腺淋巴瘤。从Brca 2（-/-）胚胎培养的成纤维细胞具有增殖缺陷，这可能是由p53和p21（Waf 1/CIP 1）的过度表达介导的。我们表明，BrcaZ是有效的DNA修复所必需的，我们的研究结果表明，p53检查点的丢失可能是BRCA 2突变引发的肿瘤进展所必需的。
Germline mutation of the BRCA2 gene carries a high risk of developing breast cancer. To study the function of this gene, we generated a mutation in Brca2 in mice, Unlike other mutations in the Brca2 gene, which are lethal early in embryogenesis when homozygous, some of our homozygous mutant mice survive to adulthood. These animals have a wide range of defects, including small size, improper differentiation of tissues, absence of germ cells and the development of lethal thymic lymphomas. Fibroblasts cultured from Brca2(-/-)embryos have a defect in proliferation that may be mediated by over-expression of p53 and p21(Waf1/CIP1). We show that BrcaZ is required for efficient DNA repair, and our results suggest that loss of the p53 checkpoint may be essential for tumour progression triggered by mutations in BRCA2.