The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells
The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells
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DOI：
10.1038/sj.onc.1210465
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发表时间：
2007-09-27
期刊：
影响因子：
8
通讯作者：
Andersen, B.
中科院分区：
文献类型：
--
作者：
Wang, N.;Lin, K. K.;Andersen, B.
核LIM-唯一蛋白4（LMO 4）在乳腺癌中上调，特别是雌激素受体阴性肿瘤，其在小鼠中的过度表达导致增生和肿瘤形成。在这里，我们表明，小鼠乳腺中LMO 4的缺失会导致上皮细胞增殖减少导致小叶肺泡发育受损。为了发现潜在的LMO 4靶基因，我们还在MCF-7细胞中开发了LMO 4及其共调节子的显性阴性（DN）形式，LIM结构域的辅因子（Clim/Ldb/Nli）的条件表达系统。然后，我们使用DNA微阵列来鉴定对LMO 4和DN-Clim上调反应的基因。两个数据集共有的基因之一是骨形态发生蛋白7（BMP 7），其表达也与人类乳腺癌的大型数据集中的LMO 4转录水平显著相关，表明BMP 7是一种良性肿瘤。目的研究LMO 4在乳腺癌中的作用。BMP 7的抑制部分阻断LMO 4对细胞凋亡的作用，表明BMP 7介导LMO 4的至少一些功能。基因转移研究表明，LMO 4调节BMP 7启动子，染色质免疫沉淀研究表明，LMO 4及其辅因子Clim 2被募集到BMP 7启动子。此外，我们证明，HDAC 2招聘到BMP 7启动子的LMO 4的上调和HDAC 2敲低上调启动子的抑制。这些研究表明LMO 4的一种新的作用机制：LMO 4，Clim 2和HDAC 2是转录复合物的一部分，增加LMO 4水平可以破坏复合物，导致HDAC 2募集减少和启动子活性增加。
The nuclear LIM-only protein 4 (LMO4) is upregulated in breast cancer, especially estrogen receptor-negative tumors, and its overexpression in mice leads to hyperplasia and tumor formation. Here, we show that deletion of LMO4 in the mammary glands of mice leads to impaired lobuloalveolar development due to decreased epithelial cell proliferation. With the goal of discovering potential LMO4-target genes, we also developed a conditional expression system in MCF-7 cells for both LMO4 and a dominant negative (DN) form of its co-regulator, cofactor of LIM domains (Clim/Ldb/Nli). We then used DNA microarrays to identify genes responsive to LMO4 and DN-Clim upregulation. One of the genes common to both data sets was bone morphogenic protein 7 (BMP7), whose expression is also significantly correlated with LMO4 transcript levels in a large dataset of human breast cancers, suggesting that BMP7 is a bona. de target gene of LMO4 in breast cancer. Inhibition of BMP7 partially blocks the effects of LMO4 on apoptosis, indicating that BMP7 mediates at least some functions of LMO4. Gene transfer studies show that LMO4 regulates the BMP7 promoter, and chromatin immunoprecipitation studies show that LMO4 and its cofactor Clim2 are recruited to the BMP7 promoter. Furthermore, we demonstrate that HDAC2 recruitment to the BMP7 promoter is inhibited by upregulation of LMO4 and that HDAC2 knockdown upregulates the promoter. These studies suggest a novel mechanism of action for LMO4: LMO4, Clim2 and HDAC2 are part of a transcriptional complex, and increased LMO4 levels can disrupt the complex, leading to decreased HDAC2 recruitment and increased promoter activity.