Regulation of DNA methyltransferase 1 by the pRb/E2F1 pathway
Regulation of DNA methyltransferase 1 by the pRb/E2F1 pathway
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DOI：
10.1158/0008-5472.can-04-2158
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Day, ML
中科院分区：
文献类型：
--
作者：
McCabe, MT;Davis, JN;Day, ML
抑癌基因沉默的DNA甲基化有助于在许多肿瘤类型的肿瘤发生。这种异常甲基化可能是由于DNA甲基转移酶的表达和活性增加，其催化甲基从S-腺苷甲硫氨酸转移到CpG二核苷酸中的胞嘧啶。维持DNA甲基转移酶，DNA甲基转移酶I（DNMT-1）的表达升高已在结肠癌、肺癌、肝癌和前列腺癌中显示。基于在人类癌症中发现的DNA甲基化和视网膜母细胞瘤蛋白（pRb）通路的几乎普遍存在的改变，我们研究了在小鼠和人前列腺上皮细胞中连接这两种改变的潜在调节通路。Rb-/-鼠前列腺上皮细胞系中DNA甲基转移酶水平的分析揭示了升高的Dnmt-1水平。基因组DNA序列分析确定了接近鼠和人Dnmt-1转录起始点的保守E2 F共有结合位点。此外，Dnmt-1启动子显示在上皮和成纤维细胞来源的鼠和人细胞系中受pRb/E2 F途径调节。在没有pRb的情况下，Dnmt-1转录物表现出异常的细胞周期调控，Rb-/-细胞表现出父系表达基因3（Peg 3）肿瘤抑制基因的异常甲基化。这些研究结果表明，在肿瘤发生中，pRb通路的失活和含CpG岛基因的DNA超甲基化诱导之间存在联系。
Tumor suppressor gene silencing by DNA hypermethylation contributes to tumorigenesis in many tumor types. This aberrant methylation may be due to increased expression and activity of DNA methyltransferases, which catalyze the transfer of methyl groups from S-adenosylmethionine to cytosines in CpG dinucleotides. Elevated expression of the maintenance DNA methyltransferase, DNA methyltransferase I (DNMT-1), has been shown in carcinomas of the colon, lung, liver, and prostate. Based on the nearly ubiquitous alterations of both DNA methylation and the retinoblastoma protein (pRb) pathway found in human cancer, we investigated a potential regulatory pathway linking the two alterations in murine and human prostate epithelial cells. Analysis of DNA methyltransferase levels in Rb-/- murine prostate epithelial cell lines revealed elevated Dnmt-1 levels. Genomic DNA sequence analysis identified conserved E2F consensus binding sites in proximity to the transcription initiation points of murine and human Dnmt-1. Furthermore, the Dnmt-1 promoter was shown to be regulated by the pRb/E2F pathway in murine and human cell lines of epithelial and fibroblast origin. In the absence of pRb, Dnmt-1 transcripts exhibited aberrant cell cycle regulation and Rb-/- cells showed aberrant methylation of the paternally expressed gene 3 (Peg3) tumor suppressor gene. These findings show a link between inactivation of the pRb pathway and induction of DNA hypermethylation of CpG island-containing genes in tumorigenesis.