Role of the AMPK-MDMX-p53 pathway in cancer

AMPK-MDMX-p53 通路在癌症中的作用

基本信息

批准号：
9753938
负责人：
Hua Lu
金额：
$ 31.2万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753938
关键词：
Accounting Address Affect Animals Antineoplastic Agents Apoptosis Autophagocytosis Binding Biochemical Biological Models Brain Hypoxia-Ischemia Cells Cellular Stress Complex Defect Development Diet Drug Targeting Energy Metabolism Event Fasting Fatty Liver Feedback Future Genes Impairment Knock-in Knock-in Mouse Lead Light Lipids Liver MDM2 gene Malignant Neoplasms Metabolic Pathway Metabolic stress Metabolism Molecular Mus Normal Cell Nuclear Nucleic Acids Nutrient Oxygen Pathway interactions Phosphorylation Phosphotransferases Physiological Play Process Protein Kinase Protein p53 Proteins Regulation Ribosomal Interaction Ribosomal Proteins Ribosomes Role STK11 gene Serine Stress TP53 gene Testing Text Tumor Suppression Weight Gain amino acid metabolism base cancer cell cell growth cellular targeting design drug discovery genetic approach glucose metabolism insight lipid metabolism nutrient deprivation public health relevance response sensor tumor tumor growth tumor metabolism tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The importance of metabolism for cancer development and progression has been increasingly recognized over the past decade. Cancer cells undergo drastic alternations of metabolism, including metabolism of glucose and lipid, and oxidative responses. These processes are highly regulated by AMPK and p53. AMPK is activated by LKB1 and AMP/ADP in response to bio-energy shortage to coordinate metabolism, cell growth, apoptosis and autophagy by phosphorylating its target proteins. Also, the tumor suppressor p53 can be activated by this type of stress to confine metabolic pathways, which favor tumor growth, and to turn on cellular pathways that lead to cell growth arrest and apoptosis by inducing a variety of genes important for these functions. The anti-tumor function of p53 is tightly regulated by its two physiological antagonists MDM2 and MDMX, which form a complex to act as a negative feedback regulator of p53. Hence, blocking this feedback regulation is the key for cellular stresses to activate p53. For instance, ribosomal stress (RS) leads to p53 activation by inducing the interaction of ribosomal proteins L11 and L5 with MDM2 and restraining the latter's activity toward p53, but defect of this interaction in MDM2C305F mice impairs this pathway. Interestingly, AMPK can act as an upstream regulator of p53 upon metabolic stress by phosphorylating MDMX at Ser342, leading to inactivation of MDMX by inducing its binding to 14-3-3, consequently activating p53. Hence, our studies suggest that MDMX may function as a crucial player under metabolic stress. Also our preliminary studies using MDM2C305F and MDMX3SA double knock-in mice showed that the double impairments of the MDM2-MDMX-p53 pathways cause significant defects of lipid and glucose metabolisms in livers upon fasting. Thus, we hypothesize that the metabolic stress-AMPK-MDMX/RS-MDM2-p53 pathways may play an important role in regulation of metabolism in both normal and cancer cells upon metabolic stress. We will test this hypothesis by addressing three specific aims. 1. To elucidate mechanisms underlying the AMPK inhibition of MDMX activity toward p53 in response to metabolic stress. A) Does S342 phosphorylation by AMPK induce nuclear localization and degradation of MDMX? B) Does S342 phosphorylation by AMPK affect the formation of the MDMX-MDM2 complex? C) Does S342 phosphorylation by AMPK induce 14-3-3-binding to S367 of MDMX? 2. To determine if the AMPK-MDMX/RS-MDM2-p53 pathways play a role in regulation of metabolism in cells and mice. A. To determine if dual defects of the MDMX-MDM2-p53 pathway impair energy metabolism under physiological and stress conditions. B. To illustrate new p53 responsive genes important for regulation of lipid and glucose metabolism by the AMPK-MDMX/RS-MDM2-p53 pathways. 3. To determine if dual defects of the AMPK-MDMX/RS-MDM2-p53 pathways accelerate tumorigenesis in two mouse tumor model systems. Completing these studies would offer molecular insight into how lipid and glucose metabolism is controlled by this pathway, and also reveal new molecule targets for future anti-cancer drug discovery.

描述（由适用提供）：在过去的十年中，新陈代谢对癌症发展和进展的重要性越来越多。癌细胞在新陈代谢的急剧替代方面，包括葡萄糖和脂质的代谢以及氧化反应。这些过程受AMPK和p53的高度调节。通过磷酸化其靶蛋白，通过LKB1和AMP/ADP激活AMPK，以响应生物能源短缺，以响应生物能力短缺，以协调代谢，细胞生长，凋亡和自噬。同样，这种类型的应力可以激活肿瘤抑制p53，以限制代谢途径，这些途径有利于肿瘤生长，并打开细胞途径，从而导致细胞生长停滞和凋亡诱导的多种基因对这些功能很重要。 p53的抗肿瘤功能受其两种物理拮抗剂MDM2和MDMX的严格调节，它们形成了一种复合物作为p53的负反馈调节剂。因此，阻止这种反馈调节是激活p53的细胞应力的关键。例如，核糖体应激（RS）通过诱导核糖体蛋白L11和L5与MDM2的相互作用而导致p53激活，并限制了后者对p53的活性，但是MDM2C305F小鼠中这种相互作用的缺陷损害了这一途径。有趣的是，AMPK可以通过在Ser342处磷酸化MDMX来充当代谢应激时p53的上游调节剂，从而通过诱导其与14-3-3的结合，从而导致MDMX失活，从而激活p53。因此，我们的研究表明，在代谢压力下，MDMX可能是至关重要的球员。同样，我们使用MDM2C305F和MDMX3SA双重敲门小鼠的初步研究表明，MDM2-MDMX-P53途径的双重损伤会在禁食后肝脏中脂质和葡萄糖代谢的严重缺陷。这就是我们假设，在代谢应激下，代谢应激 - AMPK-MDMX/RS-MDM2-P53途径在正常和癌细胞的代谢中可能起重要作用。我们将通过解决三个具体目标来检验这一假设。 1。阐明对AMPK抑制MDMX活性对p53的机制，以响应代谢应激。 A）AMPK通过AMPK磷酸化会影响MDMX的核定位和降解吗？ b）AMPK的S342磷酸化是否会影响MDMX-MDM2复合物的形成？ c）AMPK通过AMPK磷酸化是否会影响MDMX的S367 14-3-3结合？ 2。确定AMPK-MDMX/RS-MDM2-P53途径是否在细胞和小鼠的代谢调节中起作用。答：确定MDMX-MDM2-P53途径的双重缺陷是否在身体和应力条件下会损害能量代谢。 B.以AMPK-MDMX/RS-MDM2-P53途径来说明新的p53响应基因对于调节脂质和葡萄糖代谢很重要。 3。确定AMPK-MDMX/RS-MDM2-P53途径的双重缺陷是否在两个小鼠肿瘤模型系统中加速了肿瘤发生。完成这些研究将提供有关脂质和葡萄糖代谢如何由该途径控制的分子见解，并且还揭示了未来抗癌药物发现的新分子靶标。