DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16(ink4A) down-regulation.
DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16(ink4A) down-regulation.
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DNA (胞嘧啶-5)-甲基转移酶 1 作为突变 p53 确定的 p16(ink4A) 下调的介体。
DOI：
10.1007/s11373-007-9222-y
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发表时间：
2008
影响因子：
11
通讯作者：
Chuang,EricY
中科院分区：
文献类型：
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作者：
Guo,Zhanjun;Tsai,Mong-Hsun;Shiao,Yih-Horng;Chen,Li-Han;Wei,Mei-Ling;Lv,Xing;Gius,David;Little,JohnB;Mitchell,JamesB;Chuang,EricY
在癌症中，通过超甲基化的基因沉默与p53基因突变一样常见。了解mu p53与其他抑癌基因甲基化之间的关系对于阐明肿瘤发生机制至关重要。本研究采用两种不同p53状态的人同基因B淋巴母细胞系，包括野生型p53的TK 6和突变型p53的WTK 1，并进行了比较。与TK 6细胞相比，WTK 1细胞中p16 ink 4A蛋白表达水平较低，同时伴有DNA（胞嘧啶-5）-甲基转移酶1（DNMT 1）基因表达增加以及p16 ink 4A启动子的高甲基化。瞬时敲低野生型p53的siRNA实验导致TK 6细胞中DNMT 1表达增加以及p16 ink 4A蛋白表达减少。相反，siRNA敲低WTK 1细胞中的muplatin p53并不改变DNMT 1或p16 ink 4A蛋白水平。此外，突变型p53对WTK 1中DNMT 1的抑制功能的丧失是由于其与DNMT 1启动子的结合能力减弱所致。综上所述，我们为阐明突变型p53与DNMT 1的关系提供了证据。我们的研究结果表明，突变型p53失去了抑制DNMT 1表达的能力，从而提高了p16 ink 4A启动子的甲基化水平，随后下调了p16 ink 4A蛋白。
In cancer, gene silencing via hypermethylation is as common as genetic mutations in p53. Understanding the relationship between mutantp53and hypermethylation of other tumor suppressor genes is essential when elucidate mechanisms of tumor development. In this study, two isogenic human B lymphoblast cell lines with different p53 status include TK6 containing wild-typep53and WTK1 with mutantp53were used and contrasted. Lower levels of p16ink4Aprotein were detected in WTK1 cells than in TK6 cells, which were accompanied by increased DNA (cytosine-5)-methyltransferase 1 (DNMT1) gene expression as well as hypermethylation of thep16ink4Apromoter. siRNA experiments to transiently knock down wild-typep53in TK6 cells resulted in increase of DNMT1 expression as well as decrease of p16ink4Aprotein. Conversely, siRNA knockdown of mutantp53in WTK1 cells did not alter either DNMT1 or p16ink4Aprotein levels. Furthermore, loss of suppression function of mutant p53 to DNMT1 in WTK1 was caused by the attenuation of its binding ability to theDNMT1promoter. In summary, we provide evidences to elucidate the relationship between mutant p53 and DNMT1. Our results indicate that mutant p53 loses its ability to suppress DNMT1 expression, and thus enhances methylation levels of thep16ink4Apromoter and subsequently down-regulates p16ink4Aprotein.