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（由申请人提供）：p53肿瘤抑制剂在预防肿瘤发生中起关键作用。 p53通常会对各种应力信号做出反应，并且在细胞中激活p53的主要公认触发因素是由于存在癌基产物而存在DNA损伤或DNA恢复应力。一旦激活，p53可以执行不同的程序，包括衰老，凋亡和细胞周期停滞。众所周知，翻译后修饰会影响p53将细胞引导到这些不同的细胞程序的能力，这取决于信号的性质。在此应用程序中，我们研究了p53，sumoylation的A-POST翻译修饰的后果。 Sumo是一种泛素样分子，共价附着在各种靶标底物上。通过进行这些研究，我们发现sumoylat的p53调节酶，二加氧酶，ARD/ADI1的表达水平，该酶在蛋氨酸拯救途径中起作用。这是调节蛋氨酸回收利用的关键途径。该途径的一个重要副产品是S-腺苷蛋氨酸（SAM），这是所有涉及DNA和蛋白质 - 甲基转移酶的反甲基化反应的主要甲基供体。对这种代谢途径的兴趣源于几个观察结果。首先，大多数癌细胞系都是蛋氨酸依赖性的，有证据表明，MTA途径的变化占了这种依赖性。其次，SAM代谢的产物甲基噻吩并腺苷（MTA）对肿瘤细胞中改变的DNA复制和细胞周期进程具有重要影响。第三，酒精中毒的肿瘤促进作用，以及众所周知的肿瘤保护作用，例如叶叶酸酯，维生素B12和二甲胺，已与甲磺胺的代谢有关。该应用中提出的证据首次暗示p53和SUMO作为蛋氨酸代谢的潜在调节剂，通过ARD/ADI1。这种途径的调节反过来可能会改变对饮食因素的敏感性，影响SAM水平，从而导致表观遗传变化，从而提供癌症的环境。该探索性应用的范围是对这些假设的检验，并了解p53和Sumo调节蛋氨酸代谢的分子机制。通过这些研究收集的数据有可能识别一个新的循环，p53肿瘤抑制剂直接影响细胞对养分的反应，从而影响癌症的易感性。公共卫生相关性：癌症是一系列涉及遗传和表观遗传变化的异常事件的表现。通过修饰与DNA（例如染色质）和DNA本身的甲基化的蛋白质的活性，实现了表观遗传变化。产生这种变化的各种调节蛋白，包括DNA甲基转移酶，甲基-CPG结合蛋白和染色质重塑因子，利用氨基酸蛋氨酸代谢的生物产物，称为SAM SAM的反应。现在，人们可以众所周知，表观遗传事件的变化解释了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。我们已经确定了一种潜在的反馈环，典型的抑制p53可能会直接影响细胞对养分的反应，从而直接影响癌症的易感性。该应用的一般范围是更好地了解肿瘤抑制剂途径，饮食和翻译后修饰之间的联系，这些联系可能会影响表观遗传变化。