BRCA1 physically associates with p53 and stimulates its transcriptional activity
BRCA1 physically associates with p53 and stimulates its transcriptional activity
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DOI：
10.1038/sj.onc.1201932
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发表时间：
1998-04-02
期刊：
影响因子：
8
通讯作者：
El-Deiry, WS
中科院分区：
文献类型：
--
作者：
Zhang, HB;Somasundaram, K;El-Deiry, WS
BRCA 1肿瘤抑制基因突变是家族性乳腺癌和卵巢癌中最常见的改变。虽然BRCA 1是正常小鼠发育所必需的，但其肿瘤抑制功能的分子基础仍然知之甚少。我们在这里表明，BRCA 1增加了p21（WAF 1/CIP 1）和bas启动子的p53依赖性转录。我们还表明，BRCA 1和p53蛋白在体外和体内相互作用。在体外，相互作用区域定位于BRCA 1的aa 224-500和p53的C-末端结构域。肿瘤衍生的反式激活缺陷型BRCA 1突变体在p53依赖性转录的共激活中是缺陷的，并且保留p53相互作用区域的BRCA 1的截短突变体作为p53依赖性转录的显性抑制剂，BRCA 1和p53协同诱导肿瘤细胞凋亡，提示BRCA 1和p53可能协同调控基因表达，发挥抑瘤作用。
Mutations of the BRCA1 tumor suppressor gene are the most commonly detected alterations in familial breast and ovarian cancer, Although BRCA1 is required for normal mouse development, the molecular basis for its tumor suppressive function remains poorly understood, We show here that BRCA1 increases p53-dependent transcription from the p21(WAF1/CIP1) and bas promoters. We also show that BRCA1 and p53 proteins interact both in vitro and in vivo. The interacting regions map, in vitro, to aa 224-500 of BRCA1 and the C-terminal domain of p53, Tumor-derived transactivation-deficient BRCA1 mutants are defective in co-activation of p53-dependent transcription and a truncation mutant of BRCA1 that retains the p53-interacting region acts as a dominant inhibitor of p53-dependent transcription, BRCA1 and p53 cooperatively induce apoptosis of cancer cells, The results indicate that BRCA1 and p53 may coordinately regulate gene expression in their role as tumor suppressors.