Suppression of mammary carcinoma cell growth by retinoic acid:: the cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling
Suppression of mammary carcinoma cell growth by retinoic acid:: the cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling
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DOI：
10.1158/0008-5472.can-06-0989
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发表时间：
2007-01-15
期刊：
影响因子：
11.2
通讯作者：
Noy, Noa
中科院分区：
文献类型：
--
作者：
Donato, Leslie J.;Suh, Jean H.;Noy, Noa
视黄酸（RA）的抗癌活性被认为是由核RA受体（RAR）和RA结合蛋白-细胞RA结合蛋白-II（CRABP-II）介导的。在MCF-7乳腺癌细胞中，RA的生长抑制需要早期细胞周期停滞，随后诱导凋亡。在这里，我们的目的是获得对初始细胞周期反应的见解。我们发现，3- 5-h RA脉冲足以诱导2 - 4天后的生长停滞，表明RA对G（1）-S转换的抑制是由立即早期RAR靶点触发的，并且不需要在整个停滞程序中持续存在激素。表达阵列分析显示，RA诱导参与细胞周期调控的几个基因的表达，包括p53控制的抗增殖基因B细胞易位基因，成员2（Btg 2）和BTG家族成员Tob 1。我们发现，RA诱导Btg 2不需要从头蛋白质合成，并通过CRABP-II的过表达增强。此外，我们确定了一个RA反应元件中的Btg 2启动子，并表明该元件结合类维生素A X受体/RAR异源二聚体在体外，被占用的异源二聚体在细胞中，并可以驱动RA诱导的激活的报告基因。因此，Btg 2是RA信号传导的新的直接靶标。与Btg 2通过下调cyclin D1抑制细胞周期进程的报道一致，RA诱导Btg 2伴随着cyclin D1表达的显著降低。因此，观察结果表明，RA在MCF-7细胞中的抗增殖活性至少部分由Btg 2介导。
The anticarcinogenic activities of retinoic acid (RA) are believed to be mediated by the nuclear RA receptor (RAR) and by the RA-binding protein cellular RA-binding protein-II (CRABP-II). In MCF-7 mammary carcinoma cells, growth inhibition by RA entails an early cell cycle arrest followed by induction of apoptosis. Here, we aimed to obtain insights into the initial cell cycle response. We show that a 3- to 5-h RA pulse is sufficient for inducing a robust growth arrest 2 to 4 days later, demonstrating inhibition of the G(1)-S transition by RA is trigered by immediate-early RAR targets and does not require the continuous presence of the hormone throughout the arrest program. Expression array analyses revealed that RA induces the expression of several genes involved in cell cycle regulation, including the p53-controlled antiproliferative gene B-cell translocation gene, member 2 (Btg2) and the BTG family member Tob1. We show that induction of Btg2 by RA does not require de novo protein synthesis and is augmented by overexpression of CRABP-II. Additionally, we identify a RA response element in the Btg2 promoter and show that the element binds retinoid X receptor/RAR heterodimers in vitro, is occupied by the heterodimers in cells, and can drive RA-induced activation of a reporter gene. Hence, Btg2 is a novel direct target for RA signaling. In concert with the reports that Btg2 inhibits cell cycle progression by downregulating cyclin D1, induction of Btg2 by RA was accompanied by a marked decrease in cyclin D1 expression. The observations thus show that the antiproliferative activity of RA in MCF-7 cells is mediated, at least in part, by Btg2.