BARX2 and estrogen receptor-α (ESR1) coordinatelyregulate the production of alternatively spliced ESR1 isoforms and control breast cancer cell growth and invasion
BARX2 and estrogen receptor-α (ESR1) coordinatelyregulate the production of alternatively spliced ESR1 isoforms and control breast cancer cell growth and invasion
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DOI：
10.1038/sj.onc.1209529
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发表时间：
2006-08-01
期刊：
影响因子：
8
通讯作者：
Meech, R.
中科院分区：
文献类型：
--
作者：
Stevens, T. A.;Meech, R.
雌激素受体-α基因（ESR 1）先前被鉴定为MCF 7细胞中同源框转录因子BARX 2的直接靶点。在这里，我们表明，BARX 2和ESR 1蛋白结合到不同的ESR 1基因启动子和调节可变剪接的mRNA编码66和46 kDa ESR 1蛋白亚型的表达。BARX 2增加了两种ESR 1亚型的表达;然而，它对46 kDa亚型的影响更大，导致46和66 kDa蛋白质之间的比例增加。BARX 2还影响雌激素依赖性过程，如锚定非依赖性生长，并调节雌激素应答基因SOX 5、RBM 15、动力蛋白和死亡蛋白的表达。此外，BARX 2表达促进细胞侵袭并增加活性基质金属蛋白酶-9（MMP 9）的表达。BARX 2还与雌激素信号传导合作增加金属蛋白酶组织抑制剂（TIMP）基因TIMP 1和TIMP 3的表达。总的来说，这些数据表明BARX 2和ESR 1可能协调调节细胞生长，存活和侵袭途径，这些途径对乳腺癌进展至关重要。
The estrogen receptor-alpha gene (ESR1) was previously identified as a direct target of the homeobox transcription factor BARX2 in MCF7 cells. Here, we show that BARX2 and ESR1 proteins bind to different ESR1 gene promoters and regulate the expression of alternatively spliced mRNAs that encode 66 and 46 kDa ESR1 protein isoforms. BARX2 increases the expression of both ESR1 isoforms; however, it has a greater effect on the 46 kDa isoform, leading to an increased ratio between the 46 and 66 kDa proteins. BARX2 also influences estrogen-dependent processes such as anchorage-independent growth and modulates the expression of the estrogen-responsive genes SOX5, RBM15, Dynein and Mortalin. In addition, BARX2 expression promotes cellular invasion and increases the expression of active matrix metalloproteinase-9 (MMP9). BARX2 also increases the expression of the tissue inhibitor of metalloproteinase (TIMP) genes, TIMP1 and TIMP3, in cooperation with estrogen signaling. Overall, these data indicate that BARX2 and ESR1 may coordinately regulate cell growth, survival and invasion pathways that are critical to breast cancer progression.