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Mechanism of tumorigenesis by abnormal modification and regulation of intracellular molecules

细胞内分子异常修饰和调控的肿瘤发生机制

基本信息

批准号：
13214086
负责人：
NAKAO Mitsuyoshi
金额：
$ 22.53万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

In conversion of biological information from DNA to RNA and protein, these molecules are chemically modified and regulated in response to cellular conditions. The whole processes except for the DNA sequence itself are often called as epigenetic regulation in a broad sense, which includes cytosine methylation and chromatin, and posttranslational modification of proteins. Since gene function is controlled at the both DNA and protein levels, these mechanisms are frequently dysregulated in malignantly transformed and cancer cells. This research project has focused on the two regulatory mechanisms, (1) transcriptional regulation by DNA methylation and chromatin, and (2) protein modification and degradation, from the viewpoint of physiological and pathological roles in carcinogenesis. Methyl-CpG binding domain protein MBD1 represses transcription from tumor suppressor genes in cancer cells in DNA methylation-mediated manner. We found that MBD1 interacts with at least two histone methyltransferase complexes, Suv39h1-HP1 heterochromatic complex and MCAF1-SETDB1 euchromatic complex, for DNA methylation-based gene repression. During this study, we first identified MCAF1 and MCAF2 as a new epigenetic regulator family of proteins. Further, MBD1 interacts with methylpurine-DNA glycosylase to link DNA methylation and base excision repair in chromatin. Regarding protein modification, we reported that HECT-domain ubiquitin ligase hHYD ubiquitinates DNA topoisomerase II-binding protein for DNA damage response. It was also reported that PML-nuclear bodies are involved in serum response transcription of c-fos gene, and that serum response factor (SRF) is modulated by SUMO-1. Similarly, aryl hydrocarbon receptor nuclear transporter (ARNT), which is involved in chemical carcinogenesis and hypoxia-induced transcription, is modulated by SUMO conjugation system.

在生物信息从DNA到RNA和蛋白质的转换中，这些分子被化学修饰并响应于细胞条件而被调节。除了DNA序列本身以外的整个过程通常被称为广义的表观遗传调控，包括胞嘧啶甲基化和染色质甲基化以及蛋白质的翻译后修饰。由于基因功能在DNA和蛋白质水平上都受到控制，这些机制在恶性转化和癌细胞中经常失调。本研究从癌发生的生理和病理作用的观点出发，对（1）DNA甲基化和染色质的转录调节、（2）蛋白质的修饰和降解这两种调节机制进行了研究。甲基化CpG结合域蛋白MBD 1以DNA甲基化介导的方式抑制癌细胞中肿瘤抑制基因的转录。我们发现MBD 1至少与两种组蛋白甲基转移酶复合物Suv 39 h1-HP 1异染色质复合物和MCAF 1-SETDB 1常染色质复合物相互作用，进行基于DNA甲基化的基因阻遏。在这项研究中，我们首先确定了MCAF 1和MCAF 2作为一个新的表观遗传调节蛋白家族。此外，MBD 1与甲基嘌呤-DNA糖基化酶相互作用，以连接DNA甲基化和染色质中的碱基切除修复。关于蛋白质修饰，我们报道了HECT结构域泛素连接酶hHYD泛素化DNA拓扑异构酶II结合蛋白，用于DNA损伤反应。研究还发现，PML核体参与c-fos基因的血清反应转录，血清反应因子（SRF）受SUMO-1的调控。同样，参与化学致癌和缺氧诱导转录的芳烃受体核转运蛋白（ARNT）也受到SUMO缀合系统的调控。