Functional Mimicry of the p53 C-terminal Tail by the Ubiquitin-like Molecule SUMO

泛素样分子 SUMO 对 p53 C 末端尾部的功能模拟

基本信息

批准号：
7479043
负责人：
MARIA L AVANTAGGIATI
金额：
$ 20.72万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7479043
关键词：
Accounting Acetylation Affect Alcoholism Amino Acids Anabolism Animals Apoptosis Binding Proteins C-terminal Cancer cell line Cancerous Cell Cycle Arrest Cell Cycle Progression Cells Chemicals Chimera organism Chromatin Chromatin Remodeling Factor Class Condition DNA DNA Damage DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA biosynthesis Data Dependency Diet Dietary Factors Dietetics Dioxygenases Disruption Docking Enzymes Epigenetic Process Event Feedback Folate Genes Genetic Growth Human Intake Lead Lesion Link Lysine Malignant Neoplasms Metabolic Pathway Metabolism Methionine Methionine Metabolism Pathway Methylation Modification Molecular Mus Names Nature Nutrient Oncogene Proteins Oncogenic Pathway interactions Personal Satisfaction Physiological Play Polyamines Post-Translational Protein Processing Predisposition Prevention Preventive Property Protein Methyltransferases Protein p53 Proteins Public Health Rattus Reaction Recycling Regulation Role Series Signal Transduction Site Source Stress Sulfur System TP53 gene Tail Testing Time Transcriptional Regulation Tumor Suppression Tumor Suppressor Proteins Ubiquitin Ubiquitin Like Proteins Xenograft procedure Yeasts bioactive food component cell growth chemical group genetic regulatory protein interest methyl group mimicry neoplastic neoplastic cell novel polypeptide prevent programs promoter protective effect protein function reductone response senescence stem three dimensional structure tissue/cell culture transcription factor transmethylation tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The p53 tumor suppressor plays a key role in preventing tumorigenesis. p53 usually responds to various stress signals, and a major recognized trigger for activating p53 in cells is the presence of DNA damage or of DNA-replication stress due to the presence of oncogene products. Once activated, p53 can execute different programs, including senescence, apoptosis and cell cycle arrest. It is well recognized that post-translational modifications affect the ability of p53 to direct cells towards these different cellular programs, depending upon the nature of the signal. In this application we have studied the consequences of a-post-translational modifications of p53, sumoylation. SUMO is a ubiquitin-like molecule which is covalently attached to a variety of target substrates. By conducting these studies we have discovered that sumoylated p53 regulates the expression levels of an enzyme, acireductone dioxygenase, ARD/ADI1 that functions in the methionine salvage pathway. This is a key pathway that regulates the recycling of methionine. One important by-product of this pathway is S-adenosyl methionine (SAM), the major methyl donor for all trans-methylation reactions that involve DNA- and protein-methyltransferases. Interest in this metabolic pathway stems from several observations. First, the majority of cancer cell lines are methionine dependent, and there is evidence that alterations in the MTA pathway account for such dependency. Second, methylthioadenosine (MTA), a product of SAM metabolism, has important effects on DNA replication and cell cycle progression, which are altered in tumor cells. Third, the tumor-predisposing effects of alcoholism, as well as the well-known tumor-protective effects of several dietary factors, such as folates, vitamine B12 and co-balamine, have been linked to the metabolism of methionine. Evidence presented in this application implicate, for the first time, p53 and SUMO as potential modulators of the metabolism of methionine, via ARD/ADI1. Regulation of this pathway could in turn alter susceptibility to dietetic factors, affect SAM levels, and consequently, lead to epigenetic changes that provide a cancer-predisposing milieu. The scope of this exploratory application is the testing of these hypotheses and to understand the molecular mechanisms by which p53 and SUMO regulate the metabolism of methionine. Data gathered with these studies have the potential to identify a novel loop by which the p53 tumor suppressor directly influences cellular responses to nutrients and, thus, cancer predisposition. PUBLIC HEALTH RELEVANCE: Cancer is the manifestation of a series of abnormal events that involve both genetic and epigenetic changes. Epigenetic changes are achieved via modifications of the activity of proteins that are in intimate contact with the DNA, such as chromatin, and via methylation of the DNA itself. A variety of regulatory proteins that produce such changes, including DNA methyltransferases, methyl-CpG binding proteins, and chromatin remodeling factors, utilize a bio-product of the metabolism of the amino acid methionine, called SAM, for their reactions. It is now well recognized that changes in epigenetic events account for the effects of many environmental and dietetic factors on cancer predisposition. An abnormality of methylation reactions that involve both DNA and proteins is a hallmark of most cancers. We have identified a potential feedback-loop by which a prototypical tumor suppressor, p53, might directly influence cellular responses to nutrients and, thus, cancer predisposition. The general scope of this application is to develop a better understanding of the link between tumor-suppressor pathways, diet, and post-translational modifications that have the potential to influence epigenetic changes.

描述（申请人提供）：p53肿瘤抑制因子在预防肿瘤发生中发挥关键作用。 p53 通常对各种应激信号作出反应，细胞中激活 p53 的一个主要公认触发因素是由于癌基因产物的存在而导致 DNA 损伤或 DNA 复制应激的存在。一旦激活，p53 可以执行不同的程序，包括衰老、细胞凋亡和细胞周期停滞。众所周知，翻译后修饰会影响 p53 将细胞引导至这些不同细胞程序的能力，具体取决于信号的性质。在此应用中，我们研究了 p53 的翻译后修饰（sumoylation）的后果。 SUMO 是一种类泛素分子，共价连接到多种靶底物上。通过进行这些研究，我们发现苏酰化 p53 调节酶、乙酰还原酮双加氧酶、ARD/ADI1 的表达水平，该酶在蛋氨酸补救途径中发挥作用。这是调节蛋氨酸回收的关键途径。该途径的一个重要副产物是 S-腺苷甲硫氨酸 (SAM)，它是所有涉及 DNA 和蛋白质甲基转移酶的转甲基反应的主要甲基供体。对这种代谢途径的兴趣源于一些观察结果。首先，大多数癌细胞系依赖蛋氨酸，并且有证据表明 MTA 途径的改变导致了这种依赖性。其次，甲硫腺苷 (MTA) 是 SAM 代谢的产物，对 DNA 复制和细胞周期进程具有重要影响，而这些在肿瘤细胞中会发生改变。第三，酒精中毒的肿瘤诱发作用，以及叶酸、维生素 B12 和钴胺素等多种饮食因素众所周知的肿瘤保护作用，都与蛋氨酸的代谢有关。本申请中提供的证据首次表明，p53 和 SUMO 通过 ARD/ADI1 作为蛋氨酸代谢的潜在调节剂。对该通路的调节反过来可能会改变对饮食因素的易感性，影响 SAM 水平，从而导致表观遗传变化，从而提供易患癌症的环境。这一探索性应用的范围是检验这些假设并了解 p53 和 SUMO 调节蛋氨酸代谢的分子机制。这些研究收集的数据有可能确定一个新的循环，p53肿瘤抑制因子通过该循环直接影响细胞对营养物质的反应，从而影响癌症易感性。公共卫生相关性：癌症是涉及遗传和表观遗传变化的一系列异常事件的表现。表观遗传变化是通过改变与 DNA 密切接触的蛋白质（例如染色质）的活性以及 DNA 本身的甲基化来实现的。产生此类变化的多种调节蛋白，包括 DNA 甲基转移酶、甲基 CpG 结合蛋白和染色质重塑因子，均利用氨基酸蛋氨酸代谢的生物产物（称为 SAM）进行反应。现在人们普遍认识到，表观遗传事件的变化可以解释许多环境和饮食因素对癌症易感性的影响。涉及 DNA 和蛋白质的甲基化反应异常是大多数癌症的标志。我们已经确定了一个潜在的反馈回路，通过该反馈回路，原型肿瘤抑制因子 p53 可能直接影响细胞对营养物质的反应，从而影响癌症易感性。该应用的总体范围是更好地理解肿瘤抑制途径、饮食和可能影响表观遗传变化的翻译后修饰之间的联系。