BRCA1 represses amphiregulin gene expression.
BRCA1 represses amphiregulin gene expression.
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DOI：
10.1158/0008-5472.can-09-2842
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Parvin JD
中科院分区：
文献类型：
--
作者：
Lamber EP;Horwitz AA;Parvin JD
乳腺癌和卵巢癌特异性肿瘤抑制因子BRCA 1是一种转录抑制因子，也是一种依赖于启动子环境的转录激活因子。为了鉴定BRCA 1激活或抑制的基因，我们分析了BRCA 1缺失细胞的微阵列结果，并揭示了BRCA 1在转录水平上调控的一些基因。在被BRCA 1抑制的基因中，我们已经鉴定了双调蛋白（AREG）和早期生长反应-1（EGR 1）。结果表明，BRCA 1通过与AREG启动子结合直接调节AREG转录，但是我们在EGR 1启动子上未检测到BRCA 1，这表明EGR 1受BRCA 1间接调节。为了确定BRCA 1抑制AREG转录的机制，我们在AREG启动子上定位了两个独立的BRCA 1反应元件，分别位于-202/-182和+19/+122。BRCA 1缺失导致AREG蛋白的诱导。总之，我们的数据建立了BRCA 1功能丧失和AREG上调之间的联系，这是一种在乳腺癌中经常观察到的基因表达变化。
BRCA1, the breast and ovarian cancer specific tumor suppressor, is a transcriptional repressor as well as a transcriptional activator dependent on the promoter context. In order to identify the genes activated or repressed by BRCA1, we have analyzed microarray results from cells depleted of BRCA1 and revealed a number of genes regulated by BRCA1 on the level of transcription. Among the genes repressed by BRCA1 we have identified Amphiregulin (AREG) and Early Growth Response-1 (EGR1). Results indicate that BRCA1 regulates AREG transcription directly through the binding to the AREG promoter, however we could not detect BRCA1 on the EGR1 promoter, suggesting that EGR1 is indirectly regulated by BRCA1. In an attempt to indentify the mechanism of the AREG transcriptional repression by BRCA1, we have mapped two independent BRCA1-response elements on the AREG promoter located at the positions −202/−182 and +19/+122. BRCA1 depletion leads to induction of AREG protein. Taken together, our data builds the connection between BRCA1 loss of function and AREG up-regulation, a change in gene expression often observed in breast cancer.