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

描述（申请人提供）：p53肿瘤抑制因子在预防肿瘤发生中起关键作用。p53通常对各种应激信号作出反应，细胞中激活p53的一个公认的主要触发因素是由于癌基因产物的存在而导致的DNA损伤或DNA复制应激。一旦被激活，p53可以执行不同的程序，包括衰老、凋亡和细胞周期阻滞。众所周知，根据信号的性质，翻译后修饰会影响p53引导细胞进入这些不同细胞程序的能力。在这个应用中，我们研究了p53的a-翻译后修饰，sumoylation的后果。SUMO是一种泛素样分子，共价附着在多种靶底物上。通过进行这些研究，我们发现，summoylated p53调节了一种酶的表达水平，即在蛋氨酸回收途径中起作用的酸还原酮双加氧酶，ARD/ADI1。这是调节蛋氨酸循环的关键途径。该途径的一个重要副产物是s-腺苷蛋氨酸（SAM），它是所有涉及DNA和蛋白质甲基转移酶的反式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，大多数癌细胞系依赖蛋氨酸，有证据表明MTA通路的改变解释了这种依赖性。其次，甲基硫代腺苷（methylthiioadenosine， MTA）是SAM代谢的产物，对肿瘤细胞中DNA复制和细胞周期进程有重要影响。第三，酒精中毒对肿瘤的诱发作用，以及一些众所周知的饮食因素对肿瘤的保护作用，如叶酸、维生素B12和共巴拉胺，都与蛋氨酸的代谢有关。本研究首次发现p53和SUMO是通过ARD/ADI1介导蛋氨酸代谢的潜在调节剂。这一途径的调控反过来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。这个探索性应用的范围是测试这些假设，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p53肿瘤抑制因子直接影响细胞对营养物质的反应，从而影响癌症易感性的新循环。

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.