Ouchi T, Monteiro A N, August A, Aaronson S A, Hanafusa H
Laboratory of Molecular Oncology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2302-6. doi: 10.1073/pnas.95.5.2302.
Mutations in BRCA1 are present in 45% of families that segregate with susceptibility for breast cancer and in 80-90% of families with both breast and ovarian cancer. Here we report that BRCA1 stimulates artificial and genomic promoter constructs containing p53-responsive elements. This activity of BRCA1 depends on the presence of wild-type p53, which was shown by using mouse fibroblasts expressing temperature-sensitive forms of p53, or p53(+/+) and p53(-/-) fibroblasts obtained from p53 knockout mice. Furthermore, mutant forms of BRCA1 lacking the C-terminal second BRCA1 C-terminal (BRCT) domain showed reduced p53-mediated transcriptional activation. Finally, we found that BRCA1 coimmunoprecipitates with p53, in vitro and in vivo. These findings suggest a function of BRCA1 as a p53 coactivator.
在与乳腺癌易感性相关的家族中，45%存在BRCA1突变；在同时患有乳腺癌和卵巢癌的家族中，80 - 90%存在BRCA1突变。在此我们报告，BRCA1可刺激含有p53反应元件的人工和基因组启动子构建体。BRCA1的这种活性依赖于野生型p53的存在，这一点通过使用表达温度敏感型p53的小鼠成纤维细胞，或从p53基因敲除小鼠获得的p53(+/+)和p53(-/-)成纤维细胞得以证实。此外，缺乏C末端第二个BRCA1 C末端（BRCT）结构域的BRCA1突变形式显示出p53介导的转录激活作用减弱。最后，我们发现BRCA1在体外和体内均能与p53进行共免疫沉淀。这些发现提示BRCA1具有作为p53共激活因子的功能。
