Yu X, Wu L C, Bowcock A M, Aronheim A, Baer R
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
J Biol Chem. 1998 Sep 25;273(39):25388-92. doi: 10.1074/jbc.273.39.25388.
The BRCA1 tumor suppressor encodes a polypeptide with two recognizable protein motifs: a RING domain near the N terminus and two tandem BRCT domains at the C terminus. Studies of tumor-associated mutations indicate that the RING and BRCT sequences are required for BRCA1-mediated tumor suppression. In addition, recent work has shown that BRCA1 is a potent regulator of RNA transcription and that the BRCT domains are also essential for this activity. Therefore, we used the Sos recruitment system to screen for proteins that bind this critical region of BRCA1. Our results show that the BRCT domains interact in vivo with CtIP, a protein originally identified on the basis of its association with the CtBP transcriptional co-repressor. This finding suggests that BRCA1 regulates gene expression, at least in part, by modulating CtBP-mediated transcriptional repression. Moreover, the in vivo interaction between BRCA1 and CtIP is completely ablated by each of three independent tumor-associated mutations affecting the BRCT motifs of BRCA1. These results indicate that the BRCA1-CtIP interaction may be required for tumor suppression by BRCA1.
BRCA1肿瘤抑制基因编码一种具有两个可识别蛋白质基序的多肽：靠近N端的一个RING结构域和C端的两个串联BRCT结构域。对肿瘤相关突变的研究表明，RING和BRCT序列是BRCA1介导的肿瘤抑制所必需的。此外，最近的研究表明BRCA1是RNA转录的有效调节因子，并且BRCT结构域对于这种活性也是必不可少的。因此，我们使用Sos募集系统筛选与BRCA1这一关键区域结合的蛋白质。我们的结果表明，BRCT结构域在体内与CtIP相互作用，CtIP是一种最初因其与CtBP转录共抑制因子的关联而被鉴定的蛋白质。这一发现表明，BRCA1至少部分地通过调节CtBP介导的转录抑制来调控基因表达。此外，BRCA1与CtIP之间的体内相互作用被影响BRCA1的BRCT基序的三个独立肿瘤相关突变中的每一个完全消除。这些结果表明，BRCA1-CtIP相互作用可能是BRCA1发挥肿瘤抑制作用所必需的。
