Role of direct interaction in BRCA1 inhibition of estrogen receptor activity
Role of direct interaction in BRCA1 inhibition of estrogen receptor activity
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DOI：
10.1038/sj.onc.1204073
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发表时间：
2001-01-04
期刊：
影响因子：
8
通讯作者：
Rosen, EM
中科院分区：
文献类型：
--
作者：
Fan, SJ;Ma, YX;Rosen, EM
先前发现BRCA 1基因抑制人乳腺癌和前列腺癌细胞系中雌激素受体[ER-α]的转录活性。在这项研究中，我们发现乳腺癌相关的BRCA 1突变消除或降低其抑制ER-α活性的能力，并且BRCA 1蛋白的氨基和羧基末端内的结构域是抑制所必需的。在BRCA 1转基因在具有内源性野生型BRCA 1的细胞系和缺乏内源性功能性BRCA 1的乳腺癌细胞系（HCC 1937）中瞬时或稳定过表达的条件下证明了BRCA 1对ER-α活性的抑制。此外，BRCA 1阻断了人乳腺癌细胞中两种内源性雌激素调节的基因产物的表达：发现BRCA 1蛋白在体内与ER-α结合，在体外与ER-α结合，通过定位于BRCA 1氨基末端区域的雌激素非依赖性相互作用（ca，氨基酸1-300）和ER-α的保守羧基末端活化功能[AF-2]结构域。此外，几种含有氨基末端ER-α结合区的截短的BRCA 1蛋白阻断全长BRCA 1蛋白抑制ER-α活性的能力。我们的研究结果表明，BRCA 1的氨基末端与ER-α相互作用，而BRCA 1的羧基末端可能作为一个转录抑制结构域。
The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell Lines. In this study, we found that breast cancer-associated mutations of BRCA1 abolish or reduce its ability to inhibit ER-alpha activity and that domains within the amino- and carboxyl-termini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-alpha activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937), In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D, The BRCA1 protein was found to associate with ER-alpha in vivo and to bind to ER-alpha in vitro, by an estrogen-independent interaction that mapped to the amino-terminal region of BRCA1 (ca, amino acid 1-300) and the conserved carboxyl-terminal activation function [AF-2] domain of ER-alpha, Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-alpha binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-alpha activity. Our findings suggest that the amino-terminus of BRCA1 interacts with ER-alpha, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain.