Hay Trevor, Patrick Teresa, Winton Douglas, Sansom Owen J, Clarke Alan R
School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK.
Oncogene. 2005 May 26;24(23):3842-6. doi: 10.1038/sj.onc.1208533.
The gene encoding the human BRCA2 tumour suppressor is mutated in a number of different tumour types, most notably inherited breast cancers. The primary role of BRCA2 is thought to lie in the maintenance of genomic stability via its role in the homologous recombination pathway. We generated mice in which Brca2 was deleted from virtually all cells within the adult small intestine, using a CYP1A1-driven Cre-Lox approach. We noted a significant p53-dependent increase in the levels of spontaneous apoptosis which persisted for several months after removal of the gene and ultimately we observed the spontaneous deletion of Brca2-deficient stem cells. Brca2 deficiency did not lead to gross changes in intestinal physiology but did enhance sensitivity to a variety of DNA crosslinking agents. Taken together, our results indicate that Brca2 plays an important role in the response to DNA damage in the small intestine. Furthermore, we show that Brca2 deficiency results in the spontaneous deletion of stem cells, thereby protecting the small intestine against tumorigenesis.
编码人类BRCA2肿瘤抑制因子的基因在多种不同类型的肿瘤中发生突变，最显著的是遗传性乳腺癌。BRCA2的主要作用被认为在于通过其在同源重组途径中的作用来维持基因组稳定性。我们利用CYP1A1驱动的Cre-Lox方法，培育出了成年小肠内几乎所有细胞中Brca2基因被敲除的小鼠。我们注意到，在基因去除后，自发凋亡水平出现了显著的、依赖p53的增加，这种增加持续了几个月，最终我们观察到Brca2缺陷干细胞的自发缺失。Brca2缺陷并未导致肠道生理功能的明显变化，但确实增强了对多种DNA交联剂的敏感性。综合来看，我们的结果表明，Brca2在小肠对DNA损伤的反应中起重要作用。此外，我们还表明，Brca2缺陷会导致干细胞的自发缺失，从而保护小肠免受肿瘤发生。
