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（由申请人提供）：在过去的十年中，人们越来越认识到代谢对于癌症发生和进展的重要性，癌细胞经历着代谢的剧烈改变，包括葡萄糖和脂质的代谢，以及氧化反应。 AMPK 和 p53 在生物能量短缺时被 LKB1 和 AMP/ADP 激活，通过磷酸化其靶蛋白来协调代谢、细胞生长、细胞凋亡和自噬。 p53 可以被这种类型的应激激活，以限制有利于肿瘤生长的代谢途径，并通过诱导多种对这些功能重要的基因来开启导致细胞生长停滞和凋亡的细胞途径，p53 受到其严格调节。两种生理拮抗剂 MDM2 和 MDMX，形成复合物作为 p53 的负反馈调节剂，因此，阻断这种反馈调节是细胞应激激活 p53 的关键。 (RS) 通过诱导核糖体蛋白 L11 和 L5 与 MDM2 相互作用并抑制后者对 p53 的活性来导致 p53 激活，但 MDM2C305F 小鼠中这种相互作用的缺陷会损害该通路，AMPK 可以作为 p53 的上游调节剂。在代谢应激时，通过磷酸化 MDMX Ser342，诱导 MDMX 与 14-3-3 结合，从而导致 MDMX 失活，从而因此，我们的研究表明，MDMX 可能在代谢应激下发挥重要作用。我们使用 MDM2C305F 和 MDMX3SA 双敲入小鼠进行的初步研究表明，MDM2-MDMX-p53 通路的双重损伤会导致显着的缺陷。因此，我们发现代谢应激-AMPK-MDMX/RS-MDM2-p53途径可能在代谢调节中发挥重要作用。我们将通过解决三个具体目标来检验这一假设： 1. 阐明 AMPK 响应代谢应激而抑制 MDMX 活性的机制 A) AMPK 磷酸化是否会诱导核定位。 B) AMPK 引起的 S342 磷酸化是否会影响 MDMX-MDM2 复合物的形成？ C) AMPK 引起的 S342 磷酸化是否会诱导？ 14-3-3-与 MDMX 的 S367 结合？ 2. 确定 AMPK-MDMX/RS-MDM2-p53 通路是否在细胞和小鼠的代谢调节中发挥作用 A. 确定 MDMX 是否存在双重缺陷。 -MDM2-p53 通路在生理和应激条件下损害能量代谢 B. 说明新的 p53 响应基因对于 AMPK-MDMX/RS-MDM2-p53 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会加速两种小鼠肿瘤模型系统中的肿瘤发生，从而为该途径如何控制脂质和葡萄糖代谢提供分子见解。还揭示了未来抗癌药物发现的新分子靶标。