The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane Qld 4102, Australia.
Mol Cancer. 2010 May 19;9:111. doi: 10.1186/1476-4598-9-111.
We have previously demonstrated that BEX2 is differentially expressed in breast tumors and has a significant role in promoting cell survival and growth in breast cancer cells. BEX2 expression protects breast cancer cells against mitochondrial apoptosis and G1 cell cycle arrest. In this study we investigated the transcriptional regulation of BEX2 and feedback mechanisms mediating the cellular function of this gene in breast cancer.
We found a marked induction of BEX2 promoter by c-Jun and p65/RelA using luciferase reporter assays in MCF-7 cells. Furthermore, we confirmed the binding of c-Jun and p65/RelA to the BEX2 promoter using a chromatin immunoprecipitation assay. Importantly, transfections of c-Jun or p65/RelA in MCF-7 cells markedly increased the expression of BEX2 protein. Overall, these results demonstrate that BEX2 is a target gene for c-Jun and p65/RelA in breast cancer. These findings were further supported by the presence of a strong correlation between BEX2 and c-Jun expression levels in primary breast tumors. Next we demonstrated that BEX2 has a feedback mechanism with c-Jun and p65/RelA in breast cancer. In this process BEX2 expression is required for the normal phosphorylation of p65 and IkappaB alpha, and the activation of p65. Moreover, it is necessary for the phosphorylation of c-Jun and JNK kinase activity in breast cancer cells. Furthermore, using c-Jun stable lines we showed that BEX2 expression is required for c-Jun mediated induction of cyclin D1 and cell proliferation. Importantly, BEX2 down-regulation resulted in a significant increase in PP2A activity in c-Jun stable lines providing a possible underlying mechanism for the regulatory effects of BEX2 on c-Jun and JNK.
This study shows that BEX2 has a functional interplay with c-Jun and p65/RelA in breast cancer. In this process BEX2 is a target gene for c-Jun and p65/RelA and in turn regulates the phosphorylation/activity of these proteins. These suggest that BEX2 is involved in a novel feedback mechanism with significant implications for the biology of breast cancer.
我们之前已经证明，BEX2 在乳腺肿瘤中差异表达，并且在乳腺癌细胞中促进细胞存活和生长方面具有重要作用。BEX2 表达保护乳腺癌细胞免受线粒体凋亡和 G1 细胞周期阻滞。在这项研究中，我们研究了 BEX2 的转录调控以及介导该基因在乳腺癌中细胞功能的反馈机制。
我们发现 c-Jun 和 p65/RelA 通过荧光素酶报告基因分析在 MCF-7 细胞中显著诱导 BEX2 启动子。此外，我们使用染色质免疫沉淀分析证实了 c-Jun 和 p65/RelA 与 BEX2 启动子的结合。重要的是，c-Jun 或 p65/RelA 在 MCF-7 细胞中的转染显著增加了 BEX2 蛋白的表达。总的来说，这些结果表明 BEX2 是乳腺癌中 c-Jun 和 p65/RelA 的靶基因。这些发现得到了原发性乳腺癌中 BEX2 和 c-Jun 表达水平之间存在强相关性的进一步支持。接下来，我们证明了 BEX2 在乳腺癌中与 c-Jun 和 p65/RelA 具有反馈机制。在这个过程中，BEX2 的表达是 p65 和 IkappaB alpha 正常磷酸化以及 p65 激活所必需的。此外，它对于乳腺癌细胞中 c-Jun 的磷酸化和 JNK 激酶活性也是必需的。此外，我们使用 c-Jun 稳定系表明，BEX2 表达是 c-Jun 介导的 cyclin D1 和细胞增殖诱导所必需的。重要的是，BEX2 的下调导致 c-Jun 稳定系中 PP2A 活性的显著增加，为 BEX2 对 c-Jun 和 JNK 的调节作用提供了一个潜在的机制。
这项研究表明，BEX2 在乳腺癌中与 c-Jun 和 p65/RelA 具有功能相互作用。在这个过程中，BEX2 是 c-Jun 和 p65/RelA 的靶基因，反过来又调节这些蛋白的磷酸化/活性。这表明 BEX2 参与了一个新的反馈机制，对乳腺癌的生物学具有重要意义。
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