Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways
Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways
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DOI：
10.1093/nar/gkg406
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发表时间：
2003-06-15
影响因子：
14.9
通讯作者：
Shiota, K
中科院分区：
文献类型：
--
作者：
Kimura, H;Nakamura, T;Shiota, K
Dnmt 1在体内的异常表达诱导细胞改变，如转化，和Dnmt 1 mRNA的增加在c-fos-，ras-和SV 40大T抗原诱导的成纤维细胞在体外转化中起着因果作用。在这里，我们研究了Dnmt 1转录的调控。我们确定了小鼠Dnmt 1的启动子区域和主要转录起始位点，并在核心启动子区域内发现了两个重要的顺式元件。一个是E2 F结合位点，另一个是尚未鉴定的因子的结合位点。两个顺式元件的点突变降低了非转化和转化细胞中的启动子活性。因此，这两个网站在增殖细胞中的Dnmt 1转录的调节中发挥关键作用。用组蛋白去乙酰化酶的特异性抑制剂-阿司他丁A处理，可增加G（0）/G（1）阻滞的NIH 3 T3细胞中Dnmt 1启动子的活性。此外，E2 F-1和Rb的表达诱导的启动子活性的降低被逆转的Saos-2细胞的阿司他丁A处理。总之，这些数据表明，转录Dnmt 1的E2 F和其他转录因子通过E2 F-Rb-HDAC依赖性和非依赖性途径在一个复杂的方式进行调节。这些发现表明Dnmt 1是细胞增殖、细胞转化和肿瘤发生中这些途径的靶基因。
Abnormal expression of Dnmt1 in vivo induces cellular alterations such as transformation, and an increase in Dnmt1 mRNA plays a causal role in c-fos-, ras- and SV40 large T antigen-induced transformation of fibroblasts in vitro. Here, we have investigated the regulation of Dnmt1 transcription. We identified the promoter region and major transcription start sites of mouse Dnmt1 and found two important cis-elements within the core promoter region. One is an E2F binding site, and the other is a binding site for an as yet unidentified factor. Point mutations in the two cis-elements decreased promoter activity in both non-transformed and transformed cells. Thus, both sites play a critical role in regulation of Dnmt1 transcription in proliferating cells. Treatment with trichostatin A, a specific inhibitor of histone deacetylase, increased Dnmt1 promoter activity in G(0)/G(1)-arrested NIH 3T3 cells. Furthermore, the decrease in promoter activity induced by expression of E2F-1 and Rb was reversed by trichostatin A treatment of Saos-2 cells. Taken together, these data indicate that transcription of Dnmt1 is regulated in a complex fashion by E2F and other transcription factors through E2F-Rb-HDAC-dependent and - independent pathways. These findings suggest that Dnmt1 is a target gene of these pathways in cell proliferation, cell transformation and tumorigenesis.