Evidence for a transcriptional activation function of BRCA1 C-terminal region
Evidence for a transcriptional activation function of BRCA1 C-terminal region
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DOI：
10.1073/pnas.93.24.13595
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发表时间：
1996-11-26
影响因子：
11.1
通讯作者：
Hanafusa, H
中科院分区：
文献类型：
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作者：
Monteiro, ANA;August, A;Hanafusa, H
BRCA 1突变占乳腺癌高发家族的45%，占乳腺癌和卵巢癌家族的80-90%。BRCA 1蛋白包括氨基末端锌指基序以及靠近C末端的过量带负电荷的氨基酸。此外，BRCA 1含有两个核定位信号，并定位于正常细胞的细胞核。虽然这些特征表明在转录调控中的作用，但没有功能被分配给BRCA 1。在这里，我们表明，C-末端区域，包括外显子16-24（aa 1560-1863）的BRCA 1融合到GAL 4 DNA结合域可以激活转录在酵母和哺乳动物细胞。此外，我们定义的区域包括外显子21-24（氨基酸1760-1863）作为最小的反式激活结构域。在乳腺癌或卵巢癌患者中发现的C-末端区域的四种种系突变（Ala-1708 --> Glu，Gln-1756 C+，Met-1775 --> Arg，Tyr-1853 --> Stop）中的任何一种都具有明显受损的转录活性。这些数据共同强调了BRCA 1的功能之一可能是转录调节的概念。
Mutations in BRCA1 account for 45% of families with high incidence of breast cancer and for 80-90% of families with both breast and ovarian cancer. BRCA1 protein includes an amino-terminal zinc finger motif as well as an excess of negatively charged amino acids near the C terminus. In addition, BRCA1 contains two nuclear localization signals and localizes to the nucleus of normal cells. While these features suggest a role in transcriptional regulation, no function has been assigned to BRCA1. Here, we show that the C-terminal region, comprising exons 16-24 (aa 1560-1863) of BRCA1 fused to GAL4 DNA binding domain can activate transcription both in yeast and mammalian cells. Furthermore, we define the region comprising exons 21-24 (aa 1760-1863) as the minimal transactivation domain. Any one of four germ-line mutations in the C-terminal region found in patients with breast or ovarian cancer (Ala-1708 --> Glu, Gln-1756 C+, Met-1775 --> Arg, Tyr-1853 --> Stop), had markedly impaired transcription activity. Together these data underscore the notion that one of the functions of BRCA1 may be the regulation of transcription.